US20240006029A1 - Systems and methods for predicting therapy efficacy from normalized biomarker scores - Google Patents
Systems and methods for predicting therapy efficacy from normalized biomarker scores Download PDFInfo
- Publication number
- US20240006029A1 US20240006029A1 US18/460,330 US202318460330A US2024006029A1 US 20240006029 A1 US20240006029 A1 US 20240006029A1 US 202318460330 A US202318460330 A US 202318460330A US 2024006029 A1 US2024006029 A1 US 2024006029A1
- Authority
- US
- United States
- Prior art keywords
- therapy
- biomarker
- expression
- level
- scores
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000000090 biomarker Substances 0.000 title claims abstract description 915
- 238000002560 therapeutic procedure Methods 0.000 title claims abstract description 689
- 238000000034 method Methods 0.000 title claims abstract description 191
- 238000012163 sequencing technique Methods 0.000 claims abstract description 138
- 238000009826 distribution Methods 0.000 claims abstract description 67
- 238000013179 statistical model Methods 0.000 claims abstract description 21
- 108010002350 Interleukin-2 Proteins 0.000 claims abstract description 14
- 229940022399 cancer vaccine Drugs 0.000 claims abstract description 11
- 238000011122 anti-angiogenic therapy Methods 0.000 claims abstract description 10
- 230000014509 gene expression Effects 0.000 claims description 374
- 206010028980 Neoplasm Diseases 0.000 claims description 188
- 201000011510 cancer Diseases 0.000 claims description 108
- 108090000623 proteins and genes Proteins 0.000 claims description 102
- 210000004027 cell Anatomy 0.000 claims description 92
- 238000011282 treatment Methods 0.000 claims description 80
- 239000012472 biological sample Substances 0.000 claims description 54
- 238000009169 immunotherapy Methods 0.000 claims description 48
- 230000035772 mutation Effects 0.000 claims description 42
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 41
- 201000010099 disease Diseases 0.000 claims description 39
- 206010027476 Metastases Diseases 0.000 claims description 35
- 210000001744 T-lymphocyte Anatomy 0.000 claims description 35
- 210000004698 lymphocyte Anatomy 0.000 claims description 33
- 210000004985 myeloid-derived suppressor cell Anatomy 0.000 claims description 32
- 230000036470 plasma concentration Effects 0.000 claims description 32
- 238000001565 modulated differential scanning calorimetry Methods 0.000 claims description 30
- 230000009401 metastasis Effects 0.000 claims description 26
- 108010011536 PTEN Phosphohydrolase Proteins 0.000 claims description 25
- 102000005789 Vascular Endothelial Growth Factors Human genes 0.000 claims description 25
- 108010019530 Vascular Endothelial Growth Factors Proteins 0.000 claims description 23
- 102000014160 PTEN Phosphohydrolase Human genes 0.000 claims description 22
- 238000003860 storage Methods 0.000 claims description 21
- 102000004887 Transforming Growth Factor beta Human genes 0.000 claims description 19
- 108090001012 Transforming Growth Factor beta Proteins 0.000 claims description 19
- 230000000869 mutational effect Effects 0.000 claims description 19
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 claims description 19
- 108090000174 Interleukin-10 Proteins 0.000 claims description 18
- 102000003814 Interleukin-10 Human genes 0.000 claims description 18
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 claims description 17
- 108020004999 messenger RNA Proteins 0.000 claims description 17
- 230000004913 activation Effects 0.000 claims description 16
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 claims description 16
- 239000000203 mixture Substances 0.000 claims description 16
- YOHYSYJDKVYCJI-UHFFFAOYSA-N n-[3-[[6-[3-(trifluoromethyl)anilino]pyrimidin-4-yl]amino]phenyl]cyclopropanecarboxamide Chemical compound FC(F)(F)C1=CC=CC(NC=2N=CN=C(NC=3C=C(NC(=O)C4CC4)C=CC=3)C=2)=C1 YOHYSYJDKVYCJI-UHFFFAOYSA-N 0.000 claims description 16
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 15
- 210000001266 CD8-positive T-lymphocyte Anatomy 0.000 claims description 14
- 102000004889 Interleukin-6 Human genes 0.000 claims description 14
- 108090001005 Interleukin-6 Proteins 0.000 claims description 14
- 102100040678 Programmed cell death protein 1 Human genes 0.000 claims description 14
- 239000000427 antigen Substances 0.000 claims description 14
- 108091007433 antigens Proteins 0.000 claims description 14
- 102000036639 antigens Human genes 0.000 claims description 14
- 210000002966 serum Anatomy 0.000 claims description 14
- 101000808011 Homo sapiens Vascular endothelial growth factor A Proteins 0.000 claims description 13
- 102100037850 Interferon gamma Human genes 0.000 claims description 13
- 102000000588 Interleukin-2 Human genes 0.000 claims description 13
- 102100039037 Vascular endothelial growth factor A Human genes 0.000 claims description 13
- 210000002540 macrophage Anatomy 0.000 claims description 13
- 102100027314 Beta-2-microglobulin Human genes 0.000 claims description 12
- 102100027207 CD27 antigen Human genes 0.000 claims description 12
- 101000914511 Homo sapiens CD27 antigen Proteins 0.000 claims description 12
- 101000581981 Homo sapiens Neural cell adhesion molecule 1 Proteins 0.000 claims description 12
- 102100027347 Neural cell adhesion molecule 1 Human genes 0.000 claims description 12
- 101710089372 Programmed cell death protein 1 Proteins 0.000 claims description 12
- 102100033177 Vascular endothelial growth factor receptor 2 Human genes 0.000 claims description 12
- 210000003690 classically activated macrophage Anatomy 0.000 claims description 12
- 102100021943 C-C motif chemokine 2 Human genes 0.000 claims description 11
- 102100028989 C-X-C chemokine receptor type 2 Human genes 0.000 claims description 11
- 108091007854 Cdh1/Fizzy-related Proteins 0.000 claims description 11
- 102100030751 Eomesodermin homolog Human genes 0.000 claims description 11
- 102100036242 HLA class II histocompatibility antigen, DQ alpha 2 chain Human genes 0.000 claims description 11
- 101001064167 Homo sapiens Eomesodermin homolog Proteins 0.000 claims description 11
- 102100024216 Programmed cell death 1 ligand 1 Human genes 0.000 claims description 11
- 210000004185 liver Anatomy 0.000 claims description 11
- 102100035875 C-C chemokine receptor type 5 Human genes 0.000 claims description 10
- 101710149870 C-C chemokine receptor type 5 Proteins 0.000 claims description 10
- 102100025248 C-X-C motif chemokine 10 Human genes 0.000 claims description 10
- 102100036170 C-X-C motif chemokine 9 Human genes 0.000 claims description 10
- 102000038594 Cdh1/Fizzy-related Human genes 0.000 claims description 10
- 108010054147 Hemoglobins Proteins 0.000 claims description 10
- 102000001554 Hemoglobins Human genes 0.000 claims description 10
- 101000858088 Homo sapiens C-X-C motif chemokine 10 Proteins 0.000 claims description 10
- 101000947172 Homo sapiens C-X-C motif chemokine 9 Proteins 0.000 claims description 10
- 101001037256 Homo sapiens Indoleamine 2,3-dioxygenase 1 Proteins 0.000 claims description 10
- 101000984753 Homo sapiens Serine/threonine-protein kinase B-raf Proteins 0.000 claims description 10
- 102100040061 Indoleamine 2,3-dioxygenase 1 Human genes 0.000 claims description 10
- 210000004322 M2 macrophage Anatomy 0.000 claims description 10
- 102100027103 Serine/threonine-protein kinase B-raf Human genes 0.000 claims description 10
- 102100034922 T-cell surface glycoprotein CD8 alpha chain Human genes 0.000 claims description 10
- 102100024598 Tumor necrosis factor ligand superfamily member 10 Human genes 0.000 claims description 10
- 210000004369 blood Anatomy 0.000 claims description 10
- 239000008280 blood Substances 0.000 claims description 10
- 230000037361 pathway Effects 0.000 claims description 10
- 108010074051 C-Reactive Protein Proteins 0.000 claims description 9
- 102100032752 C-reactive protein Human genes 0.000 claims description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 9
- 102100027581 Forkhead box protein P3 Human genes 0.000 claims description 9
- 101000861452 Homo sapiens Forkhead box protein P3 Proteins 0.000 claims description 9
- 108010018951 Interleukin-8B Receptors Proteins 0.000 claims description 9
- 102100029193 Low affinity immunoglobulin gamma Fc region receptor III-A Human genes 0.000 claims description 9
- 102000048850 Neoplasm Genes Human genes 0.000 claims description 9
- 108700019961 Neoplasm Genes Proteins 0.000 claims description 9
- 210000004443 dendritic cell Anatomy 0.000 claims description 9
- 210000002950 fibroblast Anatomy 0.000 claims description 9
- 102100034608 Angiopoietin-2 Human genes 0.000 claims description 8
- 108010074708 B7-H1 Antigen Proteins 0.000 claims description 8
- 102100028990 C-X-C chemokine receptor type 3 Human genes 0.000 claims description 8
- 102100025279 C-X-C motif chemokine 11 Human genes 0.000 claims description 8
- 102100035793 CD83 antigen Human genes 0.000 claims description 8
- 102100024423 Carbonic anhydrase 9 Human genes 0.000 claims description 8
- 102100039498 Cytotoxic T-lymphocyte protein 4 Human genes 0.000 claims description 8
- 108010086786 HLA-DQA1 antigen Proteins 0.000 claims description 8
- 101000916050 Homo sapiens C-X-C chemokine receptor type 3 Proteins 0.000 claims description 8
- 101000858060 Homo sapiens C-X-C motif chemokine 11 Proteins 0.000 claims description 8
- 101000946856 Homo sapiens CD83 antigen Proteins 0.000 claims description 8
- 102100028123 Macrophage colony-stimulating factor 1 Human genes 0.000 claims description 8
- 210000000822 natural killer cell Anatomy 0.000 claims description 8
- 102000052609 BRCA2 Human genes 0.000 claims description 7
- 108700020462 BRCA2 Proteins 0.000 claims description 7
- 101150008921 Brca2 gene Proteins 0.000 claims description 7
- 102100025137 Early activation antigen CD69 Human genes 0.000 claims description 7
- 102100039623 Epithelial splicing regulatory protein 1 Human genes 0.000 claims description 7
- 102100020997 Fractalkine Human genes 0.000 claims description 7
- 102100036241 HLA class II histocompatibility antigen, DQ beta 1 chain Human genes 0.000 claims description 7
- 108010065026 HLA-DQB1 antigen Proteins 0.000 claims description 7
- 101000946794 Homo sapiens C-C motif chemokine 8 Proteins 0.000 claims description 7
- 101000934374 Homo sapiens Early activation antigen CD69 Proteins 0.000 claims description 7
- 101000814084 Homo sapiens Epithelial splicing regulatory protein 1 Proteins 0.000 claims description 7
- 101000854520 Homo sapiens Fractalkine Proteins 0.000 claims description 7
- 101000917858 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 claims description 7
- 101000917839 Homo sapiens Low affinity immunoglobulin gamma Fc region receptor III-B Proteins 0.000 claims description 7
- 101000622304 Homo sapiens Vascular cell adhesion protein 1 Proteins 0.000 claims description 7
- 102000004890 Interleukin-8 Human genes 0.000 claims description 7
- 108090001007 Interleukin-8 Proteins 0.000 claims description 7
- 108010050345 Microphthalmia-Associated Transcription Factor Proteins 0.000 claims description 7
- 102100030157 Microphthalmia-associated transcription factor Human genes 0.000 claims description 7
- 102100021487 Protein S100-B Human genes 0.000 claims description 7
- 108700028909 Serum Amyloid A Proteins 0.000 claims description 7
- 102000054727 Serum Amyloid A Human genes 0.000 claims description 7
- 102000000011 Syndecan-4 Human genes 0.000 claims description 7
- 108010055215 Syndecan-4 Proteins 0.000 claims description 7
- 108010060804 Toll-Like Receptor 4 Proteins 0.000 claims description 7
- 102100023543 Vascular cell adhesion protein 1 Human genes 0.000 claims description 7
- 108700020467 WT1 Proteins 0.000 claims description 7
- 102100022748 Wilms tumor protein Human genes 0.000 claims description 7
- 230000006907 apoptotic process Effects 0.000 claims description 7
- 230000002601 intratumoral effect Effects 0.000 claims description 7
- 238000012737 microarray-based gene expression Methods 0.000 claims description 7
- 238000012243 multiplex automated genomic engineering Methods 0.000 claims description 7
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 claims description 7
- 150000004043 trisaccharides Chemical class 0.000 claims description 7
- 108010048036 Angiopoietin-2 Proteins 0.000 claims description 6
- 102100034871 C-C motif chemokine 8 Human genes 0.000 claims description 6
- 102100031650 C-X-C chemokine receptor type 4 Human genes 0.000 claims description 6
- 102000001398 Granzyme Human genes 0.000 claims description 6
- 108060005986 Granzyme Proteins 0.000 claims description 6
- 101000922348 Homo sapiens C-X-C chemokine receptor type 4 Proteins 0.000 claims description 6
- 101000851018 Homo sapiens Vascular endothelial growth factor receptor 1 Proteins 0.000 claims description 6
- 101000851007 Homo sapiens Vascular endothelial growth factor receptor 2 Proteins 0.000 claims description 6
- 108700012411 TNFSF10 Proteins 0.000 claims description 6
- 102100033178 Vascular endothelial growth factor receptor 1 Human genes 0.000 claims description 6
- 230000001093 anti-cancer Effects 0.000 claims description 6
- 210000000988 bone and bone Anatomy 0.000 claims description 6
- 238000003745 diagnosis Methods 0.000 claims description 6
- 210000002889 endothelial cell Anatomy 0.000 claims description 6
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 6
- 238000007637 random forest analysis Methods 0.000 claims description 6
- 230000019491 signal transduction Effects 0.000 claims description 6
- 230000011664 signaling Effects 0.000 claims description 6
- 210000004881 tumor cell Anatomy 0.000 claims description 6
- 229960005486 vaccine Drugs 0.000 claims description 6
- 102100026413 Branched-chain-amino-acid aminotransferase, mitochondrial Human genes 0.000 claims description 5
- 108700012439 CA9 Proteins 0.000 claims description 5
- 108010009992 CD163 antigen Proteins 0.000 claims description 5
- 229940045513 CTLA4 antagonist Drugs 0.000 claims description 5
- 102100025570 Cancer/testis antigen 1 Human genes 0.000 claims description 5
- 108020004705 Codon Proteins 0.000 claims description 5
- 102100035186 DNA excision repair protein ERCC-1 Human genes 0.000 claims description 5
- 102100039788 GTPase NRas Human genes 0.000 claims description 5
- 102100021260 Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Human genes 0.000 claims description 5
- 102100033325 Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 Human genes 0.000 claims description 5
- 102100040505 HLA class II histocompatibility antigen, DR alpha chain Human genes 0.000 claims description 5
- 108010067802 HLA-DR alpha-Chains Proteins 0.000 claims description 5
- 101000766294 Homo sapiens Branched-chain-amino-acid aminotransferase, mitochondrial Proteins 0.000 claims description 5
- 101000797758 Homo sapiens C-C motif chemokine 7 Proteins 0.000 claims description 5
- 101000856237 Homo sapiens Cancer/testis antigen 1 Proteins 0.000 claims description 5
- 101000876529 Homo sapiens DNA excision repair protein ERCC-1 Proteins 0.000 claims description 5
- 101000744505 Homo sapiens GTPase NRas Proteins 0.000 claims description 5
- 101000894906 Homo sapiens Galactosylgalactosylxylosylprotein 3-beta-glucuronosyltransferase 1 Proteins 0.000 claims description 5
- 101000926793 Homo sapiens Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1 Proteins 0.000 claims description 5
- 101001137975 Homo sapiens Leucyl-cystinyl aminopeptidase Proteins 0.000 claims description 5
- 101000588145 Homo sapiens Microtubule-associated tumor suppressor 1 Proteins 0.000 claims description 5
- 101001018196 Homo sapiens Mitogen-activated protein kinase kinase kinase 5 Proteins 0.000 claims description 5
- 101001103036 Homo sapiens Nuclear receptor ROR-alpha Proteins 0.000 claims description 5
- 101001001487 Homo sapiens Phosphatidylinositol-glycan biosynthesis class F protein Proteins 0.000 claims description 5
- 101000595923 Homo sapiens Placenta growth factor Proteins 0.000 claims description 5
- 101000742883 Homo sapiens Roquin-2 Proteins 0.000 claims description 5
- 101000829436 Homo sapiens Transcription elongation factor SPT6 Proteins 0.000 claims description 5
- 101000652736 Homo sapiens Transgelin Proteins 0.000 claims description 5
- 101000614354 Homo sapiens Transmembrane prolyl 4-hydroxylase Proteins 0.000 claims description 5
- 101001103033 Homo sapiens Tyrosine-protein kinase transmembrane receptor ROR2 Proteins 0.000 claims description 5
- 101000854879 Homo sapiens V-type proton ATPase 116 kDa subunit a 2 Proteins 0.000 claims description 5
- 108010065805 Interleukin-12 Proteins 0.000 claims description 5
- 102100020872 Leucyl-cystinyl aminopeptidase Human genes 0.000 claims description 5
- 108010018650 MEF2 Transcription Factors Proteins 0.000 claims description 5
- 102100031550 Microtubule-associated tumor suppressor 1 Human genes 0.000 claims description 5
- 102100033127 Mitogen-activated protein kinase kinase kinase 5 Human genes 0.000 claims description 5
- 102100021148 Myocyte-specific enhancer factor 2A Human genes 0.000 claims description 5
- 102100035194 Placenta growth factor Human genes 0.000 claims description 5
- 102100038059 Roquin-2 Human genes 0.000 claims description 5
- 102100025831 Scavenger receptor cysteine-rich type 1 protein M130 Human genes 0.000 claims description 5
- 102100023690 Transcription elongation factor SPT6 Human genes 0.000 claims description 5
- 102100040472 Transmembrane prolyl 4-hydroxylase Human genes 0.000 claims description 5
- 102100020745 V-type proton ATPase 116 kDa subunit a 2 Human genes 0.000 claims description 5
- 150000001720 carbohydrates Chemical class 0.000 claims description 5
- 210000000265 leukocyte Anatomy 0.000 claims description 5
- 238000012417 linear regression Methods 0.000 claims description 5
- 102000004311 liver X receptors Human genes 0.000 claims description 5
- 108090000865 liver X receptors Proteins 0.000 claims description 5
- 210000001370 mediastinum Anatomy 0.000 claims description 5
- 230000001394 metastastic effect Effects 0.000 claims description 5
- 206010061289 metastatic neoplasm Diseases 0.000 claims description 5
- 238000003062 neural network model Methods 0.000 claims description 5
- 210000000440 neutrophil Anatomy 0.000 claims description 5
- 238000004062 sedimentation Methods 0.000 claims description 5
- 102000052591 Anaphase-Promoting Complex-Cyclosome Apc6 Subunit Human genes 0.000 claims description 4
- 108700004603 Anaphase-Promoting Complex-Cyclosome Apc6 Subunit Proteins 0.000 claims description 4
- 102100037435 Antiviral innate immune response receptor RIG-I Human genes 0.000 claims description 4
- 101100005736 Arabidopsis thaliana APC6 gene Proteins 0.000 claims description 4
- 102100022005 B-lymphocyte antigen CD20 Human genes 0.000 claims description 4
- 102100023702 C-C motif chemokine 13 Human genes 0.000 claims description 4
- 102100032366 C-C motif chemokine 7 Human genes 0.000 claims description 4
- 101150017278 CDC16 gene Proteins 0.000 claims description 4
- 108010021064 CTLA-4 Antigen Proteins 0.000 claims description 4
- 101100327311 Dictyostelium discoideum anapc6 gene Proteins 0.000 claims description 4
- 102400000686 Endothelin-1 Human genes 0.000 claims description 4
- 101800004490 Endothelin-1 Proteins 0.000 claims description 4
- 208000010201 Exanthema Diseases 0.000 claims description 4
- 108010001498 Galectin 1 Proteins 0.000 claims description 4
- 102100021736 Galectin-1 Human genes 0.000 claims description 4
- 102100034458 Hepatitis A virus cellular receptor 2 Human genes 0.000 claims description 4
- 101000897405 Homo sapiens B-lymphocyte antigen CD20 Proteins 0.000 claims description 4
- 101000978379 Homo sapiens C-C motif chemokine 13 Proteins 0.000 claims description 4
- 101000599852 Homo sapiens Intercellular adhesion molecule 1 Proteins 0.000 claims description 4
- 101000621037 Homo sapiens Rab-like protein 2B Proteins 0.000 claims description 4
- 101000581153 Homo sapiens Rho GTPase-activating protein 10 Proteins 0.000 claims description 4
- 101001092004 Homo sapiens Rho GTPase-activating protein 21 Proteins 0.000 claims description 4
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 claims description 4
- 101000760764 Homo sapiens Tyrosyl-DNA phosphodiesterase 1 Proteins 0.000 claims description 4
- 102100037877 Intercellular adhesion molecule 1 Human genes 0.000 claims description 4
- 108010074328 Interferon-gamma Proteins 0.000 claims description 4
- 102100024616 Platelet endothelial cell adhesion molecule Human genes 0.000 claims description 4
- 102100040120 Prominin-1 Human genes 0.000 claims description 4
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims description 4
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims description 4
- 102100022836 Rab-like protein 2B Human genes 0.000 claims description 4
- 102100035753 Rho GTPase-activating protein 21 Human genes 0.000 claims description 4
- 108010044012 STAT1 Transcription Factor Proteins 0.000 claims description 4
- 102100029904 Signal transducer and activator of transcription 1-alpha/beta Human genes 0.000 claims description 4
- 108091008874 T cell receptors Proteins 0.000 claims description 4
- 102000016266 T-Cell Antigen Receptors Human genes 0.000 claims description 4
- 208000007536 Thrombosis Diseases 0.000 claims description 4
- 102100030951 Tissue factor pathway inhibitor Human genes 0.000 claims description 4
- 102100031013 Transgelin Human genes 0.000 claims description 4
- 108010083176 Twist-Related Protein 2 Proteins 0.000 claims description 4
- 102100031720 Twist-related protein 2 Human genes 0.000 claims description 4
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 claims description 4
- 102100039616 Tyrosine-protein kinase transmembrane receptor ROR2 Human genes 0.000 claims description 4
- 102100024579 Tyrosyl-DNA phosphodiesterase 1 Human genes 0.000 claims description 4
- 230000003044 adaptive effect Effects 0.000 claims description 4
- 230000000975 bioactive effect Effects 0.000 claims description 4
- 230000007812 deficiency Effects 0.000 claims description 4
- 230000001419 dependent effect Effects 0.000 claims description 4
- 210000003979 eosinophil Anatomy 0.000 claims description 4
- 201000005884 exanthem Diseases 0.000 claims description 4
- 210000002443 helper t lymphocyte Anatomy 0.000 claims description 4
- 230000000977 initiatory effect Effects 0.000 claims description 4
- 108010013555 lipoprotein-associated coagulation inhibitor Proteins 0.000 claims description 4
- 210000003240 portal vein Anatomy 0.000 claims description 4
- 206010037844 rash Diseases 0.000 claims description 4
- 230000000284 resting effect Effects 0.000 claims description 4
- 229960004641 rituximab Drugs 0.000 claims description 4
- 230000004580 weight loss Effects 0.000 claims description 4
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 claims description 3
- 101800004616 Adrenomedullin Proteins 0.000 claims description 3
- 108700028369 Alleles Proteins 0.000 claims description 3
- 101710127675 Antiviral innate immune response receptor RIG-I Proteins 0.000 claims description 3
- 108700012434 CCL3 Proteins 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 102000000013 Chemokine CCL3 Human genes 0.000 claims description 3
- 108010055165 Chemokine CCL4 Proteins 0.000 claims description 3
- 102000001326 Chemokine CCL4 Human genes 0.000 claims description 3
- 108010035532 Collagen Proteins 0.000 claims description 3
- 102000008186 Collagen Human genes 0.000 claims description 3
- 101000836154 Homo sapiens Transforming acidic coiled-coil-containing protein 1 Proteins 0.000 claims description 3
- 108010002386 Interleukin-3 Proteins 0.000 claims description 3
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 claims description 3
- 108010081689 Osteopontin Proteins 0.000 claims description 3
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 claims description 3
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 claims description 3
- 101150094092 STAT1 gene Proteins 0.000 claims description 3
- 102100021669 Stromal cell-derived factor 1 Human genes 0.000 claims description 3
- 102100027049 Transforming acidic coiled-coil-containing protein 1 Human genes 0.000 claims description 3
- 108060008682 Tumor Necrosis Factor Proteins 0.000 claims description 3
- 208000025865 Ulcer Diseases 0.000 claims description 3
- ULCUCJFASIJEOE-NPECTJMMSA-N adrenomedullin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)NCC(=O)N[C@@H]1C(N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)NCC(=O)N[C@H](C(=O)N[C@@H](CSSC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(N)=O)[C@@H](C)O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 ULCUCJFASIJEOE-NPECTJMMSA-N 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229920001436 collagen Polymers 0.000 claims description 3
- 239000002299 complementary DNA Substances 0.000 claims description 3
- 231100000433 cytotoxic Toxicity 0.000 claims description 3
- 230000001472 cytotoxic effect Effects 0.000 claims description 3
- 230000002440 hepatic effect Effects 0.000 claims description 3
- 101150102751 mtap gene Proteins 0.000 claims description 3
- 230000036269 ulceration Effects 0.000 claims description 3
- 108010088751 Albumins Proteins 0.000 claims description 2
- 102000002260 Alkaline Phosphatase Human genes 0.000 claims description 2
- 108020004774 Alkaline Phosphatase Proteins 0.000 claims description 2
- 102100021569 Apoptosis regulator Bcl-2 Human genes 0.000 claims description 2
- 102100021631 B-cell lymphoma 6 protein Human genes 0.000 claims description 2
- 108091012583 BCL2 Proteins 0.000 claims description 2
- 102100021251 Beclin-1 Human genes 0.000 claims description 2
- 108090000524 Beclin-1 Proteins 0.000 claims description 2
- 102100037362 Fibronectin Human genes 0.000 claims description 2
- 108010067306 Fibronectins Proteins 0.000 claims description 2
- 101000971234 Homo sapiens B-cell lymphoma 6 protein Proteins 0.000 claims description 2
- 101001068133 Homo sapiens Hepatitis A virus cellular receptor 2 Proteins 0.000 claims description 2
- 101000777628 Homo sapiens Leukocyte antigen CD37 Proteins 0.000 claims description 2
- 101001018258 Homo sapiens Macrophage receptor MARCO Proteins 0.000 claims description 2
- 101000891649 Homo sapiens Transcription elongation factor A protein-like 1 Proteins 0.000 claims description 2
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 claims description 2
- 102100031586 Leukocyte antigen CD37 Human genes 0.000 claims description 2
- 101710099301 Low affinity immunoglobulin gamma Fc region receptor III-A Proteins 0.000 claims description 2
- 208000008771 Lymphadenopathy Diseases 0.000 claims description 2
- 102100033272 Macrophage receptor MARCO Human genes 0.000 claims description 2
- 108091033773 MiR-155 Proteins 0.000 claims description 2
- 102100025744 Mothers against decapentaplegic homolog 1 Human genes 0.000 claims description 2
- 102100038895 Myc proto-oncogene protein Human genes 0.000 claims description 2
- 101700032040 SMAD1 Proteins 0.000 claims description 2
- 108010017324 STAT3 Transcription Factor Proteins 0.000 claims description 2
- 102100024040 Signal transducer and activator of transcription 3 Human genes 0.000 claims description 2
- 102100025244 T-cell surface glycoprotein CD5 Human genes 0.000 claims description 2
- 102000004338 Transferrin Human genes 0.000 claims description 2
- 108090000901 Transferrin Proteins 0.000 claims description 2
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 claims description 2
- 230000002491 angiogenic effect Effects 0.000 claims description 2
- 230000003511 endothelial effect Effects 0.000 claims description 2
- 210000003630 histaminocyte Anatomy 0.000 claims description 2
- 208000018555 lymphatic system disease Diseases 0.000 claims description 2
- 238000011275 oncology therapy Methods 0.000 claims description 2
- 239000012581 transferrin Substances 0.000 claims description 2
- 239000002753 trypsin inhibitor Substances 0.000 claims description 2
- 102400001318 Adrenomedullin Human genes 0.000 claims 1
- 102000009027 Albumins Human genes 0.000 claims 1
- 101100540159 Candida albicans (strain SC5314 / ATCC MYA-2876) TFP1 gene Proteins 0.000 claims 1
- 101000872458 Homo sapiens Huntingtin-interacting protein 1-related protein Proteins 0.000 claims 1
- 102100034773 Huntingtin-interacting protein 1-related protein Human genes 0.000 claims 1
- 102000004264 Osteopontin Human genes 0.000 claims 1
- 101100316793 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) VMA1 gene Proteins 0.000 claims 1
- 101710088580 Stromal cell-derived factor 1 Proteins 0.000 claims 1
- 102000008233 Toll-Like Receptor 4 Human genes 0.000 claims 1
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 claims 1
- 230000004044 response Effects 0.000 description 113
- 208000037821 progressive disease Diseases 0.000 description 57
- 239000000523 sample Substances 0.000 description 47
- 238000005516 engineering process Methods 0.000 description 44
- 102000004169 proteins and genes Human genes 0.000 description 43
- 230000008569 process Effects 0.000 description 42
- 238000004458 analytical method Methods 0.000 description 36
- 239000002246 antineoplastic agent Substances 0.000 description 36
- 229940124597 therapeutic agent Drugs 0.000 description 34
- -1 iron) Chemical class 0.000 description 27
- 238000002626 targeted therapy Methods 0.000 description 25
- 239000003795 chemical substances by application Substances 0.000 description 23
- 108020004414 DNA Proteins 0.000 description 22
- 238000003556 assay Methods 0.000 description 19
- 238000001574 biopsy Methods 0.000 description 18
- 208000024891 symptom Diseases 0.000 description 17
- 230000000670 limiting effect Effects 0.000 description 15
- 230000005746 immune checkpoint blockade Effects 0.000 description 14
- 230000001225 therapeutic effect Effects 0.000 description 14
- 238000003384 imaging method Methods 0.000 description 13
- 101000635938 Homo sapiens Transforming growth factor beta-1 proprotein Proteins 0.000 description 12
- 102100030742 Transforming growth factor beta-1 proprotein Human genes 0.000 description 12
- 230000002068 genetic effect Effects 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 230000027455 binding Effects 0.000 description 11
- 239000011230 binding agent Substances 0.000 description 11
- 230000000007 visual effect Effects 0.000 description 11
- 230000001413 cellular effect Effects 0.000 description 10
- 239000003814 drug Substances 0.000 description 10
- 230000000694 effects Effects 0.000 description 10
- 150000007523 nucleic acids Chemical class 0.000 description 10
- 210000002381 plasma Anatomy 0.000 description 10
- 230000004083 survival effect Effects 0.000 description 10
- 102100032367 C-C motif chemokine 5 Human genes 0.000 description 9
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 9
- 101000797762 Homo sapiens C-C motif chemokine 5 Proteins 0.000 description 9
- 101000599940 Homo sapiens Interferon gamma Proteins 0.000 description 9
- 101000713602 Homo sapiens T-box transcription factor TBX21 Proteins 0.000 description 9
- 101000946843 Homo sapiens T-cell surface glycoprotein CD8 alpha chain Proteins 0.000 description 9
- 101000635958 Homo sapiens Transforming growth factor beta-2 proprotein Proteins 0.000 description 9
- 102100036840 T-box transcription factor TBX21 Human genes 0.000 description 9
- 102100030737 Transforming growth factor beta-2 proprotein Human genes 0.000 description 9
- 102000056172 Transforming growth factor beta-3 Human genes 0.000 description 9
- 108090000097 Transforming growth factor beta-3 Proteins 0.000 description 9
- 238000011161 development Methods 0.000 description 9
- 230000018109 developmental process Effects 0.000 description 9
- 102000039446 nucleic acids Human genes 0.000 description 9
- 108020004707 nucleic acids Proteins 0.000 description 9
- 238000001959 radiotherapy Methods 0.000 description 9
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 8
- 102100040247 Tumor necrosis factor Human genes 0.000 description 8
- 238000001514 detection method Methods 0.000 description 8
- 238000009396 hybridization Methods 0.000 description 8
- 238000005457 optimization Methods 0.000 description 8
- 239000002147 L01XE04 - Sunitinib Substances 0.000 description 7
- 102100023085 Serine/threonine-protein kinase mTOR Human genes 0.000 description 7
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 238000002648 combination therapy Methods 0.000 description 7
- 230000006870 function Effects 0.000 description 7
- 238000012268 genome sequencing Methods 0.000 description 7
- 230000006872 improvement Effects 0.000 description 7
- 229960001796 sunitinib Drugs 0.000 description 7
- WINHZLLDWRZWRT-ATVHPVEESA-N sunitinib Chemical compound CCN(CC)CCNC(=O)C1=C(C)NC(\C=C/2C3=CC(F)=CC=C3NC\2=O)=C1C WINHZLLDWRZWRT-ATVHPVEESA-N 0.000 description 7
- 102100036150 C-X-C motif chemokine 5 Human genes 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 6
- 108090000695 Cytokines Proteins 0.000 description 6
- 108010050568 HLA-DM antigens Proteins 0.000 description 6
- 101000897480 Homo sapiens C-C motif chemokine 2 Proteins 0.000 description 6
- 101000947186 Homo sapiens C-X-C motif chemokine 5 Proteins 0.000 description 6
- 101001055222 Homo sapiens Interleukin-8 Proteins 0.000 description 6
- 101000932478 Homo sapiens Receptor-type tyrosine-protein kinase FLT3 Proteins 0.000 description 6
- 101000742859 Homo sapiens Retinoblastoma-associated protein Proteins 0.000 description 6
- 101000819111 Homo sapiens Trans-acting T-cell-specific transcription factor GATA-3 Proteins 0.000 description 6
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 description 6
- 101000638161 Homo sapiens Tumor necrosis factor ligand superfamily member 6 Proteins 0.000 description 6
- 101001047681 Homo sapiens Tyrosine-protein kinase Lck Proteins 0.000 description 6
- 102100026236 Interleukin-8 Human genes 0.000 description 6
- 102000000440 Melanoma-associated antigen Human genes 0.000 description 6
- 108050008953 Melanoma-associated antigen Proteins 0.000 description 6
- 102100020718 Receptor-type tyrosine-protein kinase FLT3 Human genes 0.000 description 6
- 102100038042 Retinoblastoma-associated protein Human genes 0.000 description 6
- 102100021386 Trans-acting T-cell-specific transcription factor GATA-3 Human genes 0.000 description 6
- 108010078814 Tumor Suppressor Protein p53 Proteins 0.000 description 6
- 102000015098 Tumor Suppressor Protein p53 Human genes 0.000 description 6
- 102100031988 Tumor necrosis factor ligand superfamily member 6 Human genes 0.000 description 6
- 102100024036 Tyrosine-protein kinase Lck Human genes 0.000 description 6
- 101150044878 US18 gene Proteins 0.000 description 6
- 108010053099 Vascular Endothelial Growth Factor Receptor-2 Proteins 0.000 description 6
- 230000003247 decreasing effect Effects 0.000 description 6
- 238000003018 immunoassay Methods 0.000 description 6
- 201000001441 melanoma Diseases 0.000 description 6
- 229960002621 pembrolizumab Drugs 0.000 description 6
- 238000001356 surgical procedure Methods 0.000 description 6
- 239000013598 vector Substances 0.000 description 6
- 239000003981 vehicle Substances 0.000 description 6
- 206010067484 Adverse reaction Diseases 0.000 description 5
- 108091011896 CSF1 Proteins 0.000 description 5
- 101000752037 Homo sapiens Arginase-1 Proteins 0.000 description 5
- 101001128158 Homo sapiens Nanos homolog 2 Proteins 0.000 description 5
- 101001124991 Homo sapiens Nitric oxide synthase, inducible Proteins 0.000 description 5
- 101000896414 Homo sapiens Nuclear nucleic acid-binding protein C1D Proteins 0.000 description 5
- 101000605639 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Proteins 0.000 description 5
- 101001043564 Homo sapiens Prolow-density lipoprotein receptor-related protein 1 Proteins 0.000 description 5
- 101000800287 Homo sapiens Tubulointerstitial nephritis antigen-like Proteins 0.000 description 5
- 108090000176 Interleukin-13 Proteins 0.000 description 5
- 102000003816 Interleukin-13 Human genes 0.000 description 5
- 102000004388 Interleukin-4 Human genes 0.000 description 5
- 108090000978 Interleukin-4 Proteins 0.000 description 5
- 102000000743 Interleukin-5 Human genes 0.000 description 5
- 108010002616 Interleukin-5 Proteins 0.000 description 5
- 239000005517 L01XE01 - Imatinib Substances 0.000 description 5
- 101150097381 Mtor gene Proteins 0.000 description 5
- 102100029438 Nitric oxide synthase, inducible Human genes 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 5
- 102100040557 Osteopontin Human genes 0.000 description 5
- 102100038332 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform Human genes 0.000 description 5
- 108010051742 Platelet-Derived Growth Factor beta Receptor Proteins 0.000 description 5
- 102100026547 Platelet-derived growth factor receptor beta Human genes 0.000 description 5
- 102100021923 Prolow-density lipoprotein receptor-related protein 1 Human genes 0.000 description 5
- 238000003559 RNA-seq method Methods 0.000 description 5
- 102100033469 Tubulointerstitial nephritis antigen-like Human genes 0.000 description 5
- 230000006838 adverse reaction Effects 0.000 description 5
- 238000002619 cancer immunotherapy Methods 0.000 description 5
- 238000002512 chemotherapy Methods 0.000 description 5
- 230000000295 complement effect Effects 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 229960002465 dabrafenib Drugs 0.000 description 5
- BFSMGDJOXZAERB-UHFFFAOYSA-N dabrafenib Chemical compound S1C(C(C)(C)C)=NC(C=2C(=C(NS(=O)(=O)C=3C(=CC=CC=3F)F)C=CC=2)F)=C1C1=CC=NC(N)=N1 BFSMGDJOXZAERB-UHFFFAOYSA-N 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 238000001415 gene therapy Methods 0.000 description 5
- 229960002411 imatinib Drugs 0.000 description 5
- KTUFNOKKBVMGRW-UHFFFAOYSA-N imatinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 KTUFNOKKBVMGRW-UHFFFAOYSA-N 0.000 description 5
- 210000003734 kidney Anatomy 0.000 description 5
- 230000036961 partial effect Effects 0.000 description 5
- 150000003384 small molecules Chemical class 0.000 description 5
- 229960003862 vemurafenib Drugs 0.000 description 5
- GPXBXXGIAQBQNI-UHFFFAOYSA-N vemurafenib Chemical compound CCCS(=O)(=O)NC1=CC=C(F)C(C(=O)C=2C3=CC(=CN=C3NC=2)C=2C=CC(Cl)=CC=2)=C1F GPXBXXGIAQBQNI-UHFFFAOYSA-N 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 102100035290 Fibroblast growth factor 13 Human genes 0.000 description 4
- 108090000379 Fibroblast growth factor 2 Proteins 0.000 description 4
- 102100021186 Granulysin Human genes 0.000 description 4
- 102100034221 Growth-regulated alpha protein Human genes 0.000 description 4
- 101000889276 Homo sapiens Cytotoxic T-lymphocyte protein 4 Proteins 0.000 description 4
- 101001040751 Homo sapiens Granulysin Proteins 0.000 description 4
- 101001069921 Homo sapiens Growth-regulated alpha protein Proteins 0.000 description 4
- 101000863884 Homo sapiens Sialic acid-binding Ig-like lectin 8 Proteins 0.000 description 4
- 101000830565 Homo sapiens Tumor necrosis factor ligand superfamily member 10 Proteins 0.000 description 4
- 102100033810 RAC-alpha serine/threonine-protein kinase Human genes 0.000 description 4
- 102100029964 Sialic acid-binding Ig-like lectin 8 Human genes 0.000 description 4
- 102100039360 Toll-like receptor 4 Human genes 0.000 description 4
- 230000033115 angiogenesis Effects 0.000 description 4
- 230000002001 anti-metastasis Effects 0.000 description 4
- 238000013459 approach Methods 0.000 description 4
- 229960000397 bevacizumab Drugs 0.000 description 4
- 230000031018 biological processes and functions Effects 0.000 description 4
- 238000004422 calculation algorithm Methods 0.000 description 4
- 210000002358 circulating endothelial cell Anatomy 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 229960004679 doxorubicin Drugs 0.000 description 4
- 238000011156 evaluation Methods 0.000 description 4
- 238000010606 normalization Methods 0.000 description 4
- 230000000771 oncological effect Effects 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 102000040430 polynucleotide Human genes 0.000 description 4
- 108091033319 polynucleotide Proteins 0.000 description 4
- 239000002157 polynucleotide Substances 0.000 description 4
- 238000003753 real-time PCR Methods 0.000 description 4
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 4
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 4
- 210000003491 skin Anatomy 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 230000003612 virological effect Effects 0.000 description 4
- 238000007482 whole exome sequencing Methods 0.000 description 4
- 238000012070 whole genome sequencing analysis Methods 0.000 description 4
- RITKWYDZSSQNJI-INXYWQKQSA-N (2s)-n-[(2s)-1-[[(2s)-4-amino-1-[[(2s)-1-[[(2s)-1-[[2-[[(2s)-1-[[(2s)-1-[[(2s)-1-amino-1-oxo-3-phenylpropan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino] Chemical compound C([C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CC=1C=CC(O)=CC=1)C1=CC=CC=C1 RITKWYDZSSQNJI-INXYWQKQSA-N 0.000 description 3
- WEVYNIUIFUYDGI-UHFFFAOYSA-N 3-[6-[4-(trifluoromethoxy)anilino]-4-pyrimidinyl]benzamide Chemical compound NC(=O)C1=CC=CC(C=2N=CN=C(NC=3C=CC(OC(F)(F)F)=CC=3)C=2)=C1 WEVYNIUIFUYDGI-UHFFFAOYSA-N 0.000 description 3
- 108060000255 AIM2 Proteins 0.000 description 3
- 102100034580 AT-rich interactive domain-containing protein 1A Human genes 0.000 description 3
- 102000000872 ATM Human genes 0.000 description 3
- 101150020330 ATRX gene Proteins 0.000 description 3
- 102100034540 Adenomatous polyposis coli protein Human genes 0.000 description 3
- 102100031934 Adhesion G-protein coupled receptor G1 Human genes 0.000 description 3
- 102100030346 Antigen peptide transporter 1 Human genes 0.000 description 3
- 102100030343 Antigen peptide transporter 2 Human genes 0.000 description 3
- 101100339431 Arabidopsis thaliana HMGB2 gene Proteins 0.000 description 3
- 108010004586 Ataxia Telangiectasia Mutated Proteins Proteins 0.000 description 3
- 101001042041 Bos taurus Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial Proteins 0.000 description 3
- 102100024794 Breast cancer metastasis-suppressor 1 Human genes 0.000 description 3
- 102100036301 C-C chemokine receptor type 7 Human genes 0.000 description 3
- 102100036846 C-C motif chemokine 21 Human genes 0.000 description 3
- 108010014064 CCCTC-Binding Factor Proteins 0.000 description 3
- 102100024263 CD160 antigen Human genes 0.000 description 3
- 102100038077 CD226 antigen Human genes 0.000 description 3
- 101150013553 CD40 gene Proteins 0.000 description 3
- 102100032937 CD40 ligand Human genes 0.000 description 3
- 102100028914 Catenin beta-1 Human genes 0.000 description 3
- ZEOWTGPWHLSLOG-UHFFFAOYSA-N Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F Chemical compound Cc1ccc(cc1-c1ccc2c(n[nH]c2c1)-c1cnn(c1)C1CC1)C(=O)Nc1cccc(c1)C(F)(F)F ZEOWTGPWHLSLOG-UHFFFAOYSA-N 0.000 description 3
- 102100035595 Cohesin subunit SA-2 Human genes 0.000 description 3
- 102100022145 Collagen alpha-1(IV) chain Human genes 0.000 description 3
- 102100025680 Complement decay-accelerating factor Human genes 0.000 description 3
- 102100035436 Complement factor D Human genes 0.000 description 3
- 102100030886 Complement receptor type 1 Human genes 0.000 description 3
- 108010043471 Core Binding Factor Alpha 2 Subunit Proteins 0.000 description 3
- 108010009392 Cyclin-Dependent Kinase Inhibitor p16 Proteins 0.000 description 3
- 102100024812 DNA (cytosine-5)-methyltransferase 3A Human genes 0.000 description 3
- 108010024491 DNA Methyltransferase 3A Proteins 0.000 description 3
- 238000001712 DNA sequencing Methods 0.000 description 3
- 102100035784 Decorin Human genes 0.000 description 3
- 102100031780 Endonuclease Human genes 0.000 description 3
- 102100021579 Enhancer of filamentation 1 Human genes 0.000 description 3
- 101710105178 F-box/WD repeat-containing protein 7 Proteins 0.000 description 3
- 102100028138 F-box/WD repeat-containing protein 7 Human genes 0.000 description 3
- 102100023593 Fibroblast growth factor receptor 1 Human genes 0.000 description 3
- 101710182386 Fibroblast growth factor receptor 1 Proteins 0.000 description 3
- 102100023600 Fibroblast growth factor receptor 2 Human genes 0.000 description 3
- 101710182389 Fibroblast growth factor receptor 2 Proteins 0.000 description 3
- 102100027842 Fibroblast growth factor receptor 3 Human genes 0.000 description 3
- 101710182396 Fibroblast growth factor receptor 3 Proteins 0.000 description 3
- 102100029974 GTPase HRas Human genes 0.000 description 3
- 102100030708 GTPase KRas Human genes 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 102100030386 Granzyme A Human genes 0.000 description 3
- 102100030385 Granzyme B Human genes 0.000 description 3
- 102100038393 Granzyme H Human genes 0.000 description 3
- 102100038395 Granzyme K Human genes 0.000 description 3
- 102100028972 HLA class I histocompatibility antigen, A alpha chain Human genes 0.000 description 3
- 102100028976 HLA class I histocompatibility antigen, B alpha chain Human genes 0.000 description 3
- 102100028971 HLA class I histocompatibility antigen, C alpha chain Human genes 0.000 description 3
- 102100033079 HLA class II histocompatibility antigen, DM alpha chain Human genes 0.000 description 3
- 102100031258 HLA class II histocompatibility antigen, DM beta chain Human genes 0.000 description 3
- 102100031547 HLA class II histocompatibility antigen, DO alpha chain Human genes 0.000 description 3
- 102100031546 HLA class II histocompatibility antigen, DO beta chain Human genes 0.000 description 3
- 102100029966 HLA class II histocompatibility antigen, DP alpha 1 chain Human genes 0.000 description 3
- 102100031618 HLA class II histocompatibility antigen, DP beta 1 chain Human genes 0.000 description 3
- 102100036117 HLA class II histocompatibility antigen, DQ beta 2 chain Human genes 0.000 description 3
- 102100028640 HLA class II histocompatibility antigen, DR beta 5 chain Human genes 0.000 description 3
- 102100040485 HLA class II histocompatibility antigen, DRB1 beta chain Human genes 0.000 description 3
- 108010075704 HLA-A Antigens Proteins 0.000 description 3
- 108010058607 HLA-B Antigens Proteins 0.000 description 3
- 108010052199 HLA-C Antigens Proteins 0.000 description 3
- 108010093061 HLA-DPA1 antigen Proteins 0.000 description 3
- 108010045483 HLA-DPB1 antigen Proteins 0.000 description 3
- 108010081606 HLA-DQA2 antigen Proteins 0.000 description 3
- 108010039343 HLA-DRB1 Chains Proteins 0.000 description 3
- 108010016996 HLA-DRB5 Chains Proteins 0.000 description 3
- 108010009907 HLA-DRB6 antigen Proteins 0.000 description 3
- 108700010013 HMGB1 Proteins 0.000 description 3
- 101150021904 HMGB1 gene Proteins 0.000 description 3
- 102100024025 Heparanase Human genes 0.000 description 3
- 102100035108 High affinity nerve growth factor receptor Human genes 0.000 description 3
- 102100037907 High mobility group protein B1 Human genes 0.000 description 3
- 102100032742 Histone-lysine N-methyltransferase SETD2 Human genes 0.000 description 3
- 101000924266 Homo sapiens AT-rich interactive domain-containing protein 1A Proteins 0.000 description 3
- 101000924577 Homo sapiens Adenomatous polyposis coli protein Proteins 0.000 description 3
- 101000775042 Homo sapiens Adhesion G-protein coupled receptor G1 Proteins 0.000 description 3
- 101000937544 Homo sapiens Beta-2-microglobulin Proteins 0.000 description 3
- 101000761839 Homo sapiens Breast cancer metastasis-suppressor 1 Proteins 0.000 description 3
- 101000761835 Homo sapiens Breast cancer metastasis-suppressor 1-like protein Proteins 0.000 description 3
- 101000716065 Homo sapiens C-C chemokine receptor type 7 Proteins 0.000 description 3
- 101000713085 Homo sapiens C-C motif chemokine 21 Proteins 0.000 description 3
- 101000761938 Homo sapiens CD160 antigen Proteins 0.000 description 3
- 101000884298 Homo sapiens CD226 antigen Proteins 0.000 description 3
- 101000868215 Homo sapiens CD40 ligand Proteins 0.000 description 3
- 101000916173 Homo sapiens Catenin beta-1 Proteins 0.000 description 3
- 101000642968 Homo sapiens Cohesin subunit SA-2 Proteins 0.000 description 3
- 101000901150 Homo sapiens Collagen alpha-1(IV) chain Proteins 0.000 description 3
- 101000856022 Homo sapiens Complement decay-accelerating factor Proteins 0.000 description 3
- 101000727061 Homo sapiens Complement receptor type 1 Proteins 0.000 description 3
- 101001000206 Homo sapiens Decorin Proteins 0.000 description 3
- 101001095815 Homo sapiens E3 ubiquitin-protein ligase RING2 Proteins 0.000 description 3
- 101000898310 Homo sapiens Enhancer of filamentation 1 Proteins 0.000 description 3
- 101000584633 Homo sapiens GTPase HRas Proteins 0.000 description 3
- 101000584612 Homo sapiens GTPase KRas Proteins 0.000 description 3
- 101001009599 Homo sapiens Granzyme A Proteins 0.000 description 3
- 101001009603 Homo sapiens Granzyme B Proteins 0.000 description 3
- 101001033000 Homo sapiens Granzyme H Proteins 0.000 description 3
- 101001033007 Homo sapiens Granzyme K Proteins 0.000 description 3
- 101000866278 Homo sapiens HLA class II histocompatibility antigen, DO alpha chain Proteins 0.000 description 3
- 101000866281 Homo sapiens HLA class II histocompatibility antigen, DO beta chain Proteins 0.000 description 3
- 101000930799 Homo sapiens HLA class II histocompatibility antigen, DQ beta 2 chain Proteins 0.000 description 3
- 101001047819 Homo sapiens Heparanase Proteins 0.000 description 3
- 101000596894 Homo sapiens High affinity nerve growth factor receptor Proteins 0.000 description 3
- 101000654725 Homo sapiens Histone-lysine N-methyltransferase SETD2 Proteins 0.000 description 3
- 101001019455 Homo sapiens ICOS ligand Proteins 0.000 description 3
- 101000959794 Homo sapiens Interferon alpha-2 Proteins 0.000 description 3
- 101001054334 Homo sapiens Interferon beta Proteins 0.000 description 3
- 101001033249 Homo sapiens Interleukin-1 beta Proteins 0.000 description 3
- 101001010600 Homo sapiens Interleukin-12 subunit alpha Proteins 0.000 description 3
- 101000852992 Homo sapiens Interleukin-12 subunit beta Proteins 0.000 description 3
- 101001010626 Homo sapiens Interleukin-22 Proteins 0.000 description 3
- 101000852980 Homo sapiens Interleukin-23 subunit alpha Proteins 0.000 description 3
- 101000853002 Homo sapiens Interleukin-25 Proteins 0.000 description 3
- 101000960234 Homo sapiens Isocitrate dehydrogenase [NADP] cytoplasmic Proteins 0.000 description 3
- 101000945331 Homo sapiens Killer cell immunoglobulin-like receptor 2DL4 Proteins 0.000 description 3
- 101000945340 Homo sapiens Killer cell immunoglobulin-like receptor 2DS1 Proteins 0.000 description 3
- 101000945339 Homo sapiens Killer cell immunoglobulin-like receptor 2DS2 Proteins 0.000 description 3
- 101000945343 Homo sapiens Killer cell immunoglobulin-like receptor 2DS3 Proteins 0.000 description 3
- 101000945342 Homo sapiens Killer cell immunoglobulin-like receptor 2DS4 Proteins 0.000 description 3
- 101000764535 Homo sapiens Lymphotoxin-alpha Proteins 0.000 description 3
- 101000916644 Homo sapiens Macrophage colony-stimulating factor 1 receptor Proteins 0.000 description 3
- 101001134216 Homo sapiens Macrophage scavenger receptor types I and II Proteins 0.000 description 3
- 101000961414 Homo sapiens Membrane cofactor protein Proteins 0.000 description 3
- 101001057193 Homo sapiens Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Proteins 0.000 description 3
- 101001091223 Homo sapiens Metastasis-suppressor KiSS-1 Proteins 0.000 description 3
- 101001128431 Homo sapiens Myeloid-derived growth factor Proteins 0.000 description 3
- 101001109503 Homo sapiens NKG2-C type II integral membrane protein Proteins 0.000 description 3
- 101001109501 Homo sapiens NKG2-D type II integral membrane protein Proteins 0.000 description 3
- 101000589301 Homo sapiens Natural cytotoxicity triggering receptor 1 Proteins 0.000 description 3
- 101000884270 Homo sapiens Natural killer cell receptor 2B4 Proteins 0.000 description 3
- 101000582005 Homo sapiens Neuron navigator 3 Proteins 0.000 description 3
- 101000974340 Homo sapiens Nuclear receptor corepressor 1 Proteins 0.000 description 3
- 101001109719 Homo sapiens Nucleophosmin Proteins 0.000 description 3
- 101000610206 Homo sapiens Pappalysin-1 Proteins 0.000 description 3
- 101000987581 Homo sapiens Perforin-1 Proteins 0.000 description 3
- 101001126417 Homo sapiens Platelet-derived growth factor receptor alpha Proteins 0.000 description 3
- 101000983583 Homo sapiens Procathepsin L Proteins 0.000 description 3
- 101001117317 Homo sapiens Programmed cell death 1 ligand 1 Proteins 0.000 description 3
- 101001135391 Homo sapiens Prostaglandin E synthase Proteins 0.000 description 3
- 101000605122 Homo sapiens Prostaglandin G/H synthase 1 Proteins 0.000 description 3
- 101000979599 Homo sapiens Protein NKG7 Proteins 0.000 description 3
- 101000601770 Homo sapiens Protein polybromo-1 Proteins 0.000 description 3
- 101001072247 Homo sapiens Protocadherin-10 Proteins 0.000 description 3
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 3
- 101000709238 Homo sapiens Serine/threonine-protein kinase SIK1 Proteins 0.000 description 3
- 101000662909 Homo sapiens T cell receptor beta constant 1 Proteins 0.000 description 3
- 101000662902 Homo sapiens T cell receptor beta constant 2 Proteins 0.000 description 3
- 101000634846 Homo sapiens T-cell receptor-associated transmembrane adapter 1 Proteins 0.000 description 3
- 101000946863 Homo sapiens T-cell surface glycoprotein CD3 delta chain Proteins 0.000 description 3
- 101000946860 Homo sapiens T-cell surface glycoprotein CD3 epsilon chain Proteins 0.000 description 3
- 101000738413 Homo sapiens T-cell surface glycoprotein CD3 gamma chain Proteins 0.000 description 3
- 101000946833 Homo sapiens T-cell surface glycoprotein CD8 beta chain Proteins 0.000 description 3
- 101000914514 Homo sapiens T-cell-specific surface glycoprotein CD28 Proteins 0.000 description 3
- 101000914484 Homo sapiens T-lymphocyte activation antigen CD80 Proteins 0.000 description 3
- 101000702545 Homo sapiens Transcription activator BRG1 Proteins 0.000 description 3
- 101000800546 Homo sapiens Transcription factor 21 Proteins 0.000 description 3
- 101000596093 Homo sapiens Transcription initiation factor TFIID subunit 1 Proteins 0.000 description 3
- 101000679851 Homo sapiens Tumor necrosis factor receptor superfamily member 4 Proteins 0.000 description 3
- 101001050476 Homo sapiens Tyrosine-protein kinase ITK/TSK Proteins 0.000 description 3
- 101000818543 Homo sapiens Tyrosine-protein kinase ZAP-70 Proteins 0.000 description 3
- 101000740048 Homo sapiens Ubiquitin carboxyl-terminal hydrolase BAP1 Proteins 0.000 description 3
- 101000671855 Homo sapiens Ubiquitin-associated and SH3 domain-containing protein A Proteins 0.000 description 3
- 101000742596 Homo sapiens Vascular endothelial growth factor C Proteins 0.000 description 3
- 102100034980 ICOS ligand Human genes 0.000 description 3
- 102100040018 Interferon alpha-2 Human genes 0.000 description 3
- 102100026720 Interferon beta Human genes 0.000 description 3
- 102100024064 Interferon-inducible protein AIM2 Human genes 0.000 description 3
- 102100039065 Interleukin-1 beta Human genes 0.000 description 3
- 102100030698 Interleukin-12 subunit alpha Human genes 0.000 description 3
- 102100036701 Interleukin-12 subunit beta Human genes 0.000 description 3
- 108090000172 Interleukin-15 Proteins 0.000 description 3
- 102000003812 Interleukin-15 Human genes 0.000 description 3
- 102100030704 Interleukin-21 Human genes 0.000 description 3
- 102100030703 Interleukin-22 Human genes 0.000 description 3
- 102100036705 Interleukin-23 subunit alpha Human genes 0.000 description 3
- 102100036680 Interleukin-25 Human genes 0.000 description 3
- 102100039905 Isocitrate dehydrogenase [NADP] cytoplasmic Human genes 0.000 description 3
- 229910020769 KISS1 Inorganic materials 0.000 description 3
- 102100033633 Killer cell immunoglobulin-like receptor 2DL4 Human genes 0.000 description 3
- 102100033631 Killer cell immunoglobulin-like receptor 2DS1 Human genes 0.000 description 3
- 102100033630 Killer cell immunoglobulin-like receptor 2DS2 Human genes 0.000 description 3
- 102100033625 Killer cell immunoglobulin-like receptor 2DS3 Human genes 0.000 description 3
- 102100033624 Killer cell immunoglobulin-like receptor 2DS4 Human genes 0.000 description 3
- 101000740049 Latilactobacillus curvatus Bioactive peptide 1 Proteins 0.000 description 3
- 101001089108 Lotus tetragonolobus Anti-H(O) lectin Proteins 0.000 description 3
- 102100026238 Lymphotoxin-alpha Human genes 0.000 description 3
- 108010075654 MAP Kinase Kinase Kinase 1 Proteins 0.000 description 3
- 102000034655 MIF Human genes 0.000 description 3
- 108060004872 MIF Proteins 0.000 description 3
- 102100028198 Macrophage colony-stimulating factor 1 receptor Human genes 0.000 description 3
- 102100025354 Macrophage mannose receptor 1 Human genes 0.000 description 3
- 102100034184 Macrophage scavenger receptor types I and II Human genes 0.000 description 3
- 108010031099 Mannose Receptor Proteins 0.000 description 3
- 108010023335 Member 2 Subfamily B ATP Binding Cassette Transporter Proteins 0.000 description 3
- 102100039373 Membrane cofactor protein Human genes 0.000 description 3
- 102100027240 Membrane-associated guanylate kinase, WW and PDZ domain-containing protein 1 Human genes 0.000 description 3
- 102100034841 Metastasis-suppressor KiSS-1 Human genes 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 102100033115 Mitogen-activated protein kinase kinase kinase 1 Human genes 0.000 description 3
- 102100022683 NKG2-C type II integral membrane protein Human genes 0.000 description 3
- 102100022680 NKG2-D type II integral membrane protein Human genes 0.000 description 3
- 102100032870 Natural cytotoxicity triggering receptor 1 Human genes 0.000 description 3
- 102100038082 Natural killer cell receptor 2B4 Human genes 0.000 description 3
- 102000007530 Neurofibromin 1 Human genes 0.000 description 3
- 108010085793 Neurofibromin 1 Proteins 0.000 description 3
- 102100030464 Neuron navigator 3 Human genes 0.000 description 3
- 102000001759 Notch1 Receptor Human genes 0.000 description 3
- 108010029755 Notch1 Receptor Proteins 0.000 description 3
- 102100022935 Nuclear receptor corepressor 1 Human genes 0.000 description 3
- 101710153660 Nuclear receptor corepressor 2 Proteins 0.000 description 3
- 102100022678 Nucleophosmin Human genes 0.000 description 3
- 102100040156 Pappalysin-1 Human genes 0.000 description 3
- 102100028467 Perforin-1 Human genes 0.000 description 3
- 102100030485 Platelet-derived growth factor receptor alpha Human genes 0.000 description 3
- 102100026534 Procathepsin L Human genes 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 102100033076 Prostaglandin E synthase Human genes 0.000 description 3
- 102100038277 Prostaglandin G/H synthase 1 Human genes 0.000 description 3
- 102100023370 Protein NKG7 Human genes 0.000 description 3
- 102100037516 Protein polybromo-1 Human genes 0.000 description 3
- 102100036386 Protocadherin-10 Human genes 0.000 description 3
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 3
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 3
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 3
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 3
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 3
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 3
- 102100025373 Runt-related transcription factor 1 Human genes 0.000 description 3
- 102100034187 S-methyl-5'-thioadenosine phosphorylase Human genes 0.000 description 3
- 101710136206 S-methyl-5'-thioadenosine phosphorylase Proteins 0.000 description 3
- 102100032771 Serine/threonine-protein kinase SIK1 Human genes 0.000 description 3
- 101150043341 Socs3 gene Proteins 0.000 description 3
- 101710168942 Sphingosine-1-phosphate phosphatase 1 Proteins 0.000 description 3
- 102000058015 Suppressor of Cytokine Signaling 3 Human genes 0.000 description 3
- 108700027337 Suppressor of Cytokine Signaling 3 Proteins 0.000 description 3
- 102100029452 T cell receptor alpha chain constant Human genes 0.000 description 3
- 102100037272 T cell receptor beta constant 1 Human genes 0.000 description 3
- 102100037298 T cell receptor beta constant 2 Human genes 0.000 description 3
- 102100029453 T-cell receptor-associated transmembrane adapter 1 Human genes 0.000 description 3
- 102100035891 T-cell surface glycoprotein CD3 delta chain Human genes 0.000 description 3
- 102100035794 T-cell surface glycoprotein CD3 epsilon chain Human genes 0.000 description 3
- 102100037911 T-cell surface glycoprotein CD3 gamma chain Human genes 0.000 description 3
- 102100034928 T-cell surface glycoprotein CD8 beta chain Human genes 0.000 description 3
- 102100027213 T-cell-specific surface glycoprotein CD28 Human genes 0.000 description 3
- 102100027222 T-lymphocyte activation antigen CD80 Human genes 0.000 description 3
- 101800000849 Tachykinin-associated peptide 2 Proteins 0.000 description 3
- 102100031027 Transcription activator BRG1 Human genes 0.000 description 3
- 102100033121 Transcription factor 21 Human genes 0.000 description 3
- 102100035222 Transcription initiation factor TFIID subunit 1 Human genes 0.000 description 3
- 102100027671 Transcriptional repressor CTCF Human genes 0.000 description 3
- 102100022153 Tumor necrosis factor receptor superfamily member 4 Human genes 0.000 description 3
- 102100040245 Tumor necrosis factor receptor superfamily member 5 Human genes 0.000 description 3
- 102100033254 Tumor suppressor ARF Human genes 0.000 description 3
- 108010083162 Twist-Related Protein 1 Proteins 0.000 description 3
- 102100030398 Twist-related protein 1 Human genes 0.000 description 3
- 102100023345 Tyrosine-protein kinase ITK/TSK Human genes 0.000 description 3
- 102100021125 Tyrosine-protein kinase ZAP-70 Human genes 0.000 description 3
- 102100040337 Ubiquitin-associated and SH3 domain-containing protein A Human genes 0.000 description 3
- 102000056014 X-linked Nuclear Human genes 0.000 description 3
- 108700042462 X-linked Nuclear Proteins 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 238000009175 antibody therapy Methods 0.000 description 3
- 238000004364 calculation method Methods 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 3
- 230000007613 environmental effect Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 238000001476 gene delivery Methods 0.000 description 3
- 239000003102 growth factor Substances 0.000 description 3
- 108010074108 interleukin-21 Proteins 0.000 description 3
- 238000007918 intramuscular administration Methods 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229940043355 kinase inhibitor Drugs 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 238000007477 logistic regression Methods 0.000 description 3
- 238000010801 machine learning Methods 0.000 description 3
- 238000002595 magnetic resonance imaging Methods 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 238000002493 microarray Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 3
- 238000003752 polymerase chain reaction Methods 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000005740 tumor formation Effects 0.000 description 3
- 229940121358 tyrosine kinase inhibitor Drugs 0.000 description 3
- 208000016261 weight loss Diseases 0.000 description 3
- VSNHCAURESNICA-NJFSPNSNSA-N 1-oxidanylurea Chemical compound N[14C](=O)NO VSNHCAURESNICA-NJFSPNSNSA-N 0.000 description 2
- 102000010400 1-phosphatidylinositol-3-kinase activity proteins Human genes 0.000 description 2
- RTQWWZBSTRGEAV-PKHIMPSTSA-N 2-[[(2s)-2-[bis(carboxymethyl)amino]-3-[4-(methylcarbamoylamino)phenyl]propyl]-[2-[bis(carboxymethyl)amino]propyl]amino]acetic acid Chemical compound CNC(=O)NC1=CC=C(C[C@@H](CN(CC(C)N(CC(O)=O)CC(O)=O)CC(O)=O)N(CC(O)=O)CC(O)=O)C=C1 RTQWWZBSTRGEAV-PKHIMPSTSA-N 0.000 description 2
- AOJJSUZBOXZQNB-VTZDEGQISA-N 4'-epidoxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-VTZDEGQISA-N 0.000 description 2
- STQGQHZAVUOBTE-UHFFFAOYSA-N 7-Cyan-hept-2t-en-4,6-diinsaeure Natural products C1=2C(O)=C3C(=O)C=4C(OC)=CC=CC=4C(=O)C3=C(O)C=2CC(O)(C(C)=O)CC1OC1CC(N)C(O)C(C)O1 STQGQHZAVUOBTE-UHFFFAOYSA-N 0.000 description 2
- 102100036732 Actin, aortic smooth muscle Human genes 0.000 description 2
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 2
- 206010052747 Adenocarcinoma pancreas Diseases 0.000 description 2
- 102000004379 Adrenomedullin Human genes 0.000 description 2
- 102100034594 Angiopoietin-1 Human genes 0.000 description 2
- 102100022014 Angiopoietin-1 receptor Human genes 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 102000004000 Aurora Kinase A Human genes 0.000 description 2
- 108090000461 Aurora Kinase A Proteins 0.000 description 2
- 102100032306 Aurora kinase B Human genes 0.000 description 2
- 102100029822 B- and T-lymphocyte attenuator Human genes 0.000 description 2
- 102100027205 B-cell antigen receptor complex-associated protein alpha chain Human genes 0.000 description 2
- 102100027203 B-cell antigen receptor complex-associated protein beta chain Human genes 0.000 description 2
- 102100038080 B-cell receptor CD22 Human genes 0.000 description 2
- 102100024222 B-lymphocyte antigen CD19 Human genes 0.000 description 2
- 102100031151 C-C chemokine receptor type 2 Human genes 0.000 description 2
- 101710149815 C-C chemokine receptor type 2 Proteins 0.000 description 2
- 102100024167 C-C chemokine receptor type 3 Human genes 0.000 description 2
- 101710149862 C-C chemokine receptor type 3 Proteins 0.000 description 2
- 101710149863 C-C chemokine receptor type 4 Proteins 0.000 description 2
- 102100036849 C-C motif chemokine 24 Human genes 0.000 description 2
- 102100021935 C-C motif chemokine 26 Human genes 0.000 description 2
- 102100021942 C-C motif chemokine 28 Human genes 0.000 description 2
- 102100025277 C-X-C motif chemokine 13 Human genes 0.000 description 2
- 102100039398 C-X-C motif chemokine 2 Human genes 0.000 description 2
- 102100032976 CCR4-NOT transcription complex subunit 6 Human genes 0.000 description 2
- 102100029761 Cadherin-5 Human genes 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 2
- 208000017897 Carcinoma of esophagus Diseases 0.000 description 2
- 102100025975 Cathepsin G Human genes 0.000 description 2
- 102100037633 Centrin-3 Human genes 0.000 description 2
- 102000006573 Chemokine CXCL12 Human genes 0.000 description 2
- 108010008951 Chemokine CXCL12 Proteins 0.000 description 2
- 102000009410 Chemokine receptor Human genes 0.000 description 2
- 108050000299 Chemokine receptor Proteins 0.000 description 2
- 102000019034 Chemokines Human genes 0.000 description 2
- 108010012236 Chemokines Proteins 0.000 description 2
- 102100024539 Chymase Human genes 0.000 description 2
- 208000030808 Clear cell renal carcinoma Diseases 0.000 description 2
- 102100033601 Collagen alpha-1(I) chain Human genes 0.000 description 2
- 102100031457 Collagen alpha-1(V) chain Human genes 0.000 description 2
- 102100031519 Collagen alpha-1(VI) chain Human genes 0.000 description 2
- 102100036213 Collagen alpha-2(I) chain Human genes 0.000 description 2
- 102100031518 Collagen alpha-2(VI) chain Human genes 0.000 description 2
- 102100024338 Collagen alpha-3(VI) chain Human genes 0.000 description 2
- 102100032768 Complement receptor type 2 Human genes 0.000 description 2
- 206010011224 Cough Diseases 0.000 description 2
- 108010058546 Cyclin D1 Proteins 0.000 description 2
- 108010024986 Cyclin-Dependent Kinase 2 Proteins 0.000 description 2
- 108010025464 Cyclin-Dependent Kinase 4 Proteins 0.000 description 2
- 108010025468 Cyclin-Dependent Kinase 6 Proteins 0.000 description 2
- 102100036239 Cyclin-dependent kinase 2 Human genes 0.000 description 2
- 102100036252 Cyclin-dependent kinase 4 Human genes 0.000 description 2
- 102100026804 Cyclin-dependent kinase 6 Human genes 0.000 description 2
- 102100025621 Cytochrome b-245 heavy chain Human genes 0.000 description 2
- 102100030960 DNA replication licensing factor MCM2 Human genes 0.000 description 2
- 102100033720 DNA replication licensing factor MCM6 Human genes 0.000 description 2
- 206010061818 Disease progression Diseases 0.000 description 2
- 102100031480 Dual specificity mitogen-activated protein kinase kinase 1 Human genes 0.000 description 2
- 102100023266 Dual specificity mitogen-activated protein kinase kinase 2 Human genes 0.000 description 2
- 238000002965 ELISA Methods 0.000 description 2
- 102100038083 Endosialin Human genes 0.000 description 2
- 102100036448 Endothelial PAS domain-containing protein 1 Human genes 0.000 description 2
- 102100040618 Eosinophil cationic protein Human genes 0.000 description 2
- 102100028471 Eosinophil peroxidase Human genes 0.000 description 2
- 102100023688 Eotaxin Human genes 0.000 description 2
- 102220569904 Epidermal growth factor receptor_R521K_mutation Human genes 0.000 description 2
- HTIJFSOGRVMCQR-UHFFFAOYSA-N Epirubicin Natural products COc1cccc2C(=O)c3c(O)c4CC(O)(CC(OC5CC(N)C(=O)C(C)O5)c4c(O)c3C(=O)c12)C(=O)CO HTIJFSOGRVMCQR-UHFFFAOYSA-N 0.000 description 2
- 102100031690 Erythroid transcription factor Human genes 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102100021056 Ferroptosis suppressor protein 1 Human genes 0.000 description 2
- 102100028071 Fibroblast growth factor 7 Human genes 0.000 description 2
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 2
- 102100024165 G1/S-specific cyclin-D1 Human genes 0.000 description 2
- 102100037858 G1/S-specific cyclin-E1 Human genes 0.000 description 2
- 102100032340 G2/mitotic-specific cyclin-B1 Human genes 0.000 description 2
- 101710088083 Glomulin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000058063 Glucose Transporter Type 1 Human genes 0.000 description 2
- 102100039619 Granulocyte colony-stimulating factor Human genes 0.000 description 2
- 102100039620 Granulocyte-macrophage colony-stimulating factor Human genes 0.000 description 2
- 108010007707 Hepatitis A Virus Cellular Receptor 2 Proteins 0.000 description 2
- 102100038009 High affinity immunoglobulin epsilon receptor subunit beta Human genes 0.000 description 2
- 102100030309 Homeobox protein Hox-A1 Human genes 0.000 description 2
- 101000929319 Homo sapiens Actin, aortic smooth muscle Proteins 0.000 description 2
- 101000924552 Homo sapiens Angiopoietin-1 Proteins 0.000 description 2
- 101000753291 Homo sapiens Angiopoietin-1 receptor Proteins 0.000 description 2
- 101000924533 Homo sapiens Angiopoietin-2 Proteins 0.000 description 2
- 101000798306 Homo sapiens Aurora kinase B Proteins 0.000 description 2
- 101000864344 Homo sapiens B- and T-lymphocyte attenuator Proteins 0.000 description 2
- 101000914489 Homo sapiens B-cell antigen receptor complex-associated protein alpha chain Proteins 0.000 description 2
- 101000914491 Homo sapiens B-cell antigen receptor complex-associated protein beta chain Proteins 0.000 description 2
- 101000884305 Homo sapiens B-cell receptor CD22 Proteins 0.000 description 2
- 101000980825 Homo sapiens B-lymphocyte antigen CD19 Proteins 0.000 description 2
- 101001095043 Homo sapiens Bone marrow proteoglycan Proteins 0.000 description 2
- 101000713078 Homo sapiens C-C motif chemokine 24 Proteins 0.000 description 2
- 101000897493 Homo sapiens C-C motif chemokine 26 Proteins 0.000 description 2
- 101000897477 Homo sapiens C-C motif chemokine 28 Proteins 0.000 description 2
- 101000858064 Homo sapiens C-X-C motif chemokine 13 Proteins 0.000 description 2
- 101000889128 Homo sapiens C-X-C motif chemokine 2 Proteins 0.000 description 2
- 101100275686 Homo sapiens CR2 gene Proteins 0.000 description 2
- 101000794587 Homo sapiens Cadherin-5 Proteins 0.000 description 2
- 101000910338 Homo sapiens Carbonic anhydrase 9 Proteins 0.000 description 2
- 101000933179 Homo sapiens Cathepsin G Proteins 0.000 description 2
- 101000880522 Homo sapiens Centrin-3 Proteins 0.000 description 2
- 101000909983 Homo sapiens Chymase Proteins 0.000 description 2
- 101000941708 Homo sapiens Collagen alpha-1(V) chain Proteins 0.000 description 2
- 101000941581 Homo sapiens Collagen alpha-1(VI) chain Proteins 0.000 description 2
- 101000875067 Homo sapiens Collagen alpha-2(I) chain Proteins 0.000 description 2
- 101000941585 Homo sapiens Collagen alpha-2(VI) chain Proteins 0.000 description 2
- 101000909506 Homo sapiens Collagen alpha-3(VI) chain Proteins 0.000 description 2
- 101000737554 Homo sapiens Complement factor D Proteins 0.000 description 2
- 101000583807 Homo sapiens DNA replication licensing factor MCM2 Proteins 0.000 description 2
- 101001018484 Homo sapiens DNA replication licensing factor MCM6 Proteins 0.000 description 2
- 101001018431 Homo sapiens DNA replication licensing factor MCM7 Proteins 0.000 description 2
- 101000884275 Homo sapiens Endosialin Proteins 0.000 description 2
- 101000967216 Homo sapiens Eosinophil cationic protein Proteins 0.000 description 2
- 101000987586 Homo sapiens Eosinophil peroxidase Proteins 0.000 description 2
- 101000978392 Homo sapiens Eotaxin Proteins 0.000 description 2
- 101001066268 Homo sapiens Erythroid transcription factor Proteins 0.000 description 2
- 101000818014 Homo sapiens Ferroptosis suppressor protein 1 Proteins 0.000 description 2
- 101001060261 Homo sapiens Fibroblast growth factor 7 Proteins 0.000 description 2
- 101000738568 Homo sapiens G1/S-specific cyclin-E1 Proteins 0.000 description 2
- 101000868643 Homo sapiens G2/mitotic-specific cyclin-B1 Proteins 0.000 description 2
- 101000746367 Homo sapiens Granulocyte colony-stimulating factor Proteins 0.000 description 2
- 101000746373 Homo sapiens Granulocyte-macrophage colony-stimulating factor Proteins 0.000 description 2
- 101000878594 Homo sapiens High affinity immunoglobulin epsilon receptor subunit beta Proteins 0.000 description 2
- 101001083156 Homo sapiens Homeobox protein Hox-A1 Proteins 0.000 description 2
- 101001046870 Homo sapiens Hypoxia-inducible factor 1-alpha Proteins 0.000 description 2
- 101000599951 Homo sapiens Insulin-like growth factor I Proteins 0.000 description 2
- 101001076292 Homo sapiens Insulin-like growth factor II Proteins 0.000 description 2
- 101001033312 Homo sapiens Interleukin-4 receptor subunit alpha Proteins 0.000 description 2
- 101000960936 Homo sapiens Interleukin-5 receptor subunit alpha Proteins 0.000 description 2
- 101000945346 Homo sapiens Killer cell immunoglobulin-like receptor 2DS5 Proteins 0.000 description 2
- 101000716729 Homo sapiens Kit ligand Proteins 0.000 description 2
- 101001090713 Homo sapiens L-lactate dehydrogenase A chain Proteins 0.000 description 2
- 101001137987 Homo sapiens Lymphocyte activation gene 3 protein Proteins 0.000 description 2
- 101000604998 Homo sapiens Lysosome-associated membrane glycoprotein 3 Proteins 0.000 description 2
- 101000573522 Homo sapiens MAP kinase-interacting serine/threonine-protein kinase 1 Proteins 0.000 description 2
- 101001018978 Homo sapiens MAP kinase-interacting serine/threonine-protein kinase 2 Proteins 0.000 description 2
- 101000896657 Homo sapiens Mitotic checkpoint serine/threonine-protein kinase BUB1 Proteins 0.000 description 2
- 101001114673 Homo sapiens Multimerin-1 Proteins 0.000 description 2
- 101000593405 Homo sapiens Myb-related protein B Proteins 0.000 description 2
- 101001090860 Homo sapiens Myeloblastin Proteins 0.000 description 2
- 101000934338 Homo sapiens Myeloid cell surface antigen CD33 Proteins 0.000 description 2
- 101000938705 Homo sapiens N-acetyltransferase ESCO2 Proteins 0.000 description 2
- 101001128156 Homo sapiens Nanos homolog 3 Proteins 0.000 description 2
- 101000851058 Homo sapiens Neutrophil elastase Proteins 0.000 description 2
- 101001124309 Homo sapiens Nitric oxide synthase, endothelial Proteins 0.000 description 2
- 101000711744 Homo sapiens Non-secretory ribonuclease Proteins 0.000 description 2
- 101001131990 Homo sapiens Peroxidasin homolog Proteins 0.000 description 2
- 101001120056 Homo sapiens Phosphatidylinositol 3-kinase regulatory subunit alpha Proteins 0.000 description 2
- 101000595741 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Proteins 0.000 description 2
- 101000595746 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Proteins 0.000 description 2
- 101000595751 Homo sapiens Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Proteins 0.000 description 2
- 101000582986 Homo sapiens Phospholipid phosphatase-related protein type 3 Proteins 0.000 description 2
- 101000611888 Homo sapiens Platelet-derived growth factor C Proteins 0.000 description 2
- 101001117312 Homo sapiens Programmed cell death 1 ligand 2 Proteins 0.000 description 2
- 101000611936 Homo sapiens Programmed cell death protein 1 Proteins 0.000 description 2
- 101000861587 Homo sapiens Protein farnesyltransferase subunit beta Proteins 0.000 description 2
- 101000877589 Homo sapiens Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha Proteins 0.000 description 2
- 101001051777 Homo sapiens Protein kinase C alpha type Proteins 0.000 description 2
- 101001123334 Homo sapiens Proteoglycan 3 Proteins 0.000 description 2
- 101000779418 Homo sapiens RAC-alpha serine/threonine-protein kinase Proteins 0.000 description 2
- 101000798015 Homo sapiens RAC-beta serine/threonine-protein kinase Proteins 0.000 description 2
- 101000798007 Homo sapiens RAC-gamma serine/threonine-protein kinase Proteins 0.000 description 2
- 101000884271 Homo sapiens Signal transducer CD24 Proteins 0.000 description 2
- 101000617130 Homo sapiens Stromal cell-derived factor 1 Proteins 0.000 description 2
- 101000904152 Homo sapiens Transcription factor E2F1 Proteins 0.000 description 2
- 101000795074 Homo sapiens Tryptase alpha/beta-1 Proteins 0.000 description 2
- 101000795167 Homo sapiens Tumor necrosis factor receptor superfamily member 13B Proteins 0.000 description 2
- 101000795169 Homo sapiens Tumor necrosis factor receptor superfamily member 13C Proteins 0.000 description 2
- 101000801255 Homo sapiens Tumor necrosis factor receptor superfamily member 17 Proteins 0.000 description 2
- 101000801232 Homo sapiens Tumor necrosis factor receptor superfamily member 1B Proteins 0.000 description 2
- 101000984551 Homo sapiens Tyrosine-protein kinase Blk Proteins 0.000 description 2
- 101000666896 Homo sapiens V-type immunoglobulin domain-containing suppressor of T-cell activation Proteins 0.000 description 2
- 101000742579 Homo sapiens Vascular endothelial growth factor B Proteins 0.000 description 2
- 101000633054 Homo sapiens Zinc finger protein SNAI2 Proteins 0.000 description 2
- 102100022875 Hypoxia-inducible factor 1-alpha Human genes 0.000 description 2
- 108060003951 Immunoglobulin Proteins 0.000 description 2
- 102100037852 Insulin-like growth factor I Human genes 0.000 description 2
- 102100025947 Insulin-like growth factor II Human genes 0.000 description 2
- 108010050904 Interferons Proteins 0.000 description 2
- 102000014150 Interferons Human genes 0.000 description 2
- 102100039078 Interleukin-4 receptor subunit alpha Human genes 0.000 description 2
- 102100039881 Interleukin-5 receptor subunit alpha Human genes 0.000 description 2
- 102000000704 Interleukin-7 Human genes 0.000 description 2
- 108010002586 Interleukin-7 Proteins 0.000 description 2
- 102000015696 Interleukins Human genes 0.000 description 2
- 108010063738 Interleukins Proteins 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- 102100033626 Killer cell immunoglobulin-like receptor 2DS5 Human genes 0.000 description 2
- 102100020880 Kit ligand Human genes 0.000 description 2
- 102100034671 L-lactate dehydrogenase A chain Human genes 0.000 description 2
- 101710159002 L-lactate oxidase Proteins 0.000 description 2
- 239000003798 L01XE11 - Pazopanib Substances 0.000 description 2
- 102000017578 LAG3 Human genes 0.000 description 2
- 102100038213 Lysosome-associated membrane glycoprotein 3 Human genes 0.000 description 2
- 108010068342 MAP Kinase Kinase 1 Proteins 0.000 description 2
- 108010068353 MAP Kinase Kinase 2 Proteins 0.000 description 2
- 102100026299 MAP kinase-interacting serine/threonine-protein kinase 1 Human genes 0.000 description 2
- 102100033610 MAP kinase-interacting serine/threonine-protein kinase 2 Human genes 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 102100030612 Mast cell carboxypeptidase A Human genes 0.000 description 2
- 206010027480 Metastatic malignant melanoma Diseases 0.000 description 2
- 108090000744 Mitogen-Activated Protein Kinase Kinases Proteins 0.000 description 2
- 102000004232 Mitogen-Activated Protein Kinase Kinases Human genes 0.000 description 2
- 102100021691 Mitotic checkpoint serine/threonine-protein kinase BUB1 Human genes 0.000 description 2
- 108091006676 Monovalent cation:proton antiporter-3 Proteins 0.000 description 2
- 102100023354 Multimerin-1 Human genes 0.000 description 2
- 101100275687 Mus musculus Cr2 gene Proteins 0.000 description 2
- 102100034670 Myb-related protein B Human genes 0.000 description 2
- 102100034681 Myeloblastin Human genes 0.000 description 2
- 102100025243 Myeloid cell surface antigen CD33 Human genes 0.000 description 2
- NWIBSHFKIJFRCO-WUDYKRTCSA-N Mytomycin Chemical compound C1N2C(C(C(C)=C(N)C3=O)=O)=C3[C@@H](COC(N)=O)[C@@]2(OC)[C@@H]2[C@H]1N2 NWIBSHFKIJFRCO-WUDYKRTCSA-N 0.000 description 2
- 102100030822 N-acetyltransferase ESCO2 Human genes 0.000 description 2
- 108010082739 NADPH Oxidase 2 Proteins 0.000 description 2
- 108091061960 Naked DNA Proteins 0.000 description 2
- 102100031893 Nanos homolog 3 Human genes 0.000 description 2
- 102000015336 Nerve Growth Factor Human genes 0.000 description 2
- 108010025020 Nerve Growth Factor Proteins 0.000 description 2
- 102100033174 Neutrophil elastase Human genes 0.000 description 2
- 102100034217 Non-secretory ribonuclease Human genes 0.000 description 2
- 206010030155 Oesophageal carcinoma Diseases 0.000 description 2
- 239000012270 PD-1 inhibitor Substances 0.000 description 2
- 239000012668 PD-1-inhibitor Substances 0.000 description 2
- 108091007960 PI3Ks Proteins 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- 102100034601 Peroxidasin homolog Human genes 0.000 description 2
- 102100026169 Phosphatidylinositol 3-kinase regulatory subunit alpha Human genes 0.000 description 2
- 102100036061 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform Human genes 0.000 description 2
- 102100036056 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform Human genes 0.000 description 2
- 102100036052 Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform Human genes 0.000 description 2
- 102100040681 Platelet-derived growth factor C Human genes 0.000 description 2
- 108010000598 Polycomb Repressive Complex 1 Proteins 0.000 description 2
- 241000288906 Primates Species 0.000 description 2
- 102100024213 Programmed cell death 1 ligand 2 Human genes 0.000 description 2
- 102100023832 Prolyl endopeptidase FAP Human genes 0.000 description 2
- 206010060862 Prostate cancer Diseases 0.000 description 2
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 2
- 102100027569 Protein farnesyltransferase subunit beta Human genes 0.000 description 2
- 102100035480 Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha Human genes 0.000 description 2
- 102100024924 Protein kinase C alpha type Human genes 0.000 description 2
- 102100033947 Protein regulator of cytokinesis 1 Human genes 0.000 description 2
- 102100026858 Protein-lysine 6-oxidase Human genes 0.000 description 2
- 102100032315 RAC-beta serine/threonine-protein kinase Human genes 0.000 description 2
- 102100032314 RAC-gamma serine/threonine-protein kinase Human genes 0.000 description 2
- 206010038019 Rectal adenocarcinoma Diseases 0.000 description 2
- 108091006296 SLC2A1 Proteins 0.000 description 2
- 102100031463 Serine/threonine-protein kinase PLK1 Human genes 0.000 description 2
- 102100038081 Signal transducer CD24 Human genes 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 208000034254 Squamous cell carcinoma of the cervix uteri Diseases 0.000 description 2
- 108010065917 TOR Serine-Threonine Kinases Proteins 0.000 description 2
- 208000033781 Thyroid carcinoma Diseases 0.000 description 2
- 208000024770 Thyroid neoplasm Diseases 0.000 description 2
- 102000040945 Transcription factor Human genes 0.000 description 2
- 108091023040 Transcription factor Proteins 0.000 description 2
- 102100024026 Transcription factor E2F1 Human genes 0.000 description 2
- 102100029639 Tryptase alpha/beta-1 Human genes 0.000 description 2
- 102100029675 Tumor necrosis factor receptor superfamily member 13B Human genes 0.000 description 2
- 102100029690 Tumor necrosis factor receptor superfamily member 13C Human genes 0.000 description 2
- 102100033726 Tumor necrosis factor receptor superfamily member 17 Human genes 0.000 description 2
- 102100033733 Tumor necrosis factor receptor superfamily member 1B Human genes 0.000 description 2
- 102100027053 Tyrosine-protein kinase Blk Human genes 0.000 description 2
- 102100038282 V-type immunoglobulin domain-containing suppressor of T-cell activation Human genes 0.000 description 2
- 101150045640 VWF gene Proteins 0.000 description 2
- 102100038217 Vascular endothelial growth factor B Human genes 0.000 description 2
- 102100038232 Vascular endothelial growth factor C Human genes 0.000 description 2
- 102100029570 Zinc finger protein SNAI2 Human genes 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 238000011374 additional therapy Methods 0.000 description 2
- 208000020990 adrenal cortex carcinoma Diseases 0.000 description 2
- 208000007128 adrenocortical carcinoma Diseases 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 108010029483 alpha 1 Chain Collagen Type I Proteins 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000011319 anticancer therapy Methods 0.000 description 2
- 230000030741 antigen processing and presentation Effects 0.000 description 2
- 229950002916 avelumab Drugs 0.000 description 2
- 210000003719 b-lymphocyte Anatomy 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 206010005084 bladder transitional cell carcinoma Diseases 0.000 description 2
- 201000001528 bladder urothelial carcinoma Diseases 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000004159 blood analysis Methods 0.000 description 2
- 238000009534 blood test Methods 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 210000001185 bone marrow Anatomy 0.000 description 2
- 210000000481 breast Anatomy 0.000 description 2
- 229960000455 brentuximab vedotin Drugs 0.000 description 2
- 210000000621 bronchi Anatomy 0.000 description 2
- 229960004562 carboplatin Drugs 0.000 description 2
- YAYRGNWWLMLWJE-UHFFFAOYSA-L carboplatin Chemical compound O=C1O[Pt](N)(N)OC(=O)C11CCC1 YAYRGNWWLMLWJE-UHFFFAOYSA-L 0.000 description 2
- 239000000969 carrier Substances 0.000 description 2
- 230000021164 cell adhesion Effects 0.000 description 2
- 238000002659 cell therapy Methods 0.000 description 2
- 201000006612 cervical squamous cell carcinoma Diseases 0.000 description 2
- 210000003679 cervix uteri Anatomy 0.000 description 2
- HJWLJNBZVZDLAQ-HAQNSBGRSA-N chembl2103874 Chemical compound C1C[C@@H](CS(=O)(=O)NC)CC[C@@H]1N(C)C1=NC=NC2=C1C=CN2 HJWLJNBZVZDLAQ-HAQNSBGRSA-N 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 208000006990 cholangiocarcinoma Diseases 0.000 description 2
- 229960004316 cisplatin Drugs 0.000 description 2
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 description 2
- 206010073251 clear cell renal cell carcinoma Diseases 0.000 description 2
- 230000006690 co-activation Effects 0.000 description 2
- 201000010897 colon adenocarcinoma Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 238000011443 conventional therapy Methods 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 208000030381 cutaneous melanoma Diseases 0.000 description 2
- 210000001151 cytotoxic T lymphocyte Anatomy 0.000 description 2
- 229960000975 daunorubicin Drugs 0.000 description 2
- STQGQHZAVUOBTE-VGBVRHCVSA-N daunorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(C)=O)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 STQGQHZAVUOBTE-VGBVRHCVSA-N 0.000 description 2
- 230000001934 delay Effects 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- FOCAHLGSDWHSAH-UHFFFAOYSA-N difluoromethanethione Chemical compound FC(F)=S FOCAHLGSDWHSAH-UHFFFAOYSA-N 0.000 description 2
- 230000005750 disease progression Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 229950009791 durvalumab Drugs 0.000 description 2
- 239000012636 effector Substances 0.000 description 2
- 201000003683 endocervical adenocarcinoma Diseases 0.000 description 2
- 108010018033 endothelial PAS domain-containing protein 1 Proteins 0.000 description 2
- 229960001904 epirubicin Drugs 0.000 description 2
- 201000005619 esophageal carcinoma Diseases 0.000 description 2
- 210000003238 esophagus Anatomy 0.000 description 2
- LZCLXQDLBQLTDK-UHFFFAOYSA-N ethyl 2-hydroxypropanoate Chemical compound CCOC(=O)C(C)O LZCLXQDLBQLTDK-UHFFFAOYSA-N 0.000 description 2
- 230000007717 exclusion Effects 0.000 description 2
- 239000013604 expression vector Substances 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- 238000000684 flow cytometry Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 229960002949 fluorouracil Drugs 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 2
- 229960005277 gemcitabine Drugs 0.000 description 2
- SDUQYLNIPVEERB-QPPQHZFASA-N gemcitabine Chemical compound O=C1N=C(N)C=CN1[C@H]1C(F)(F)[C@H](O)[C@@H](CO)O1 SDUQYLNIPVEERB-QPPQHZFASA-N 0.000 description 2
- 238000012224 gene deletion Methods 0.000 description 2
- 230000004547 gene signature Effects 0.000 description 2
- 210000003714 granulocyte Anatomy 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 2
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 2
- 150000002391 heterocyclic compounds Chemical class 0.000 description 2
- 229960001001 ibritumomab tiuxetan Drugs 0.000 description 2
- 210000002865 immune cell Anatomy 0.000 description 2
- 210000000987 immune system Anatomy 0.000 description 2
- 102000018358 immunoglobulin Human genes 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 208000024312 invasive carcinoma Diseases 0.000 description 2
- 229960005386 ipilimumab Drugs 0.000 description 2
- 238000002357 laparoscopic surgery Methods 0.000 description 2
- 208000032839 leukemia Diseases 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 201000005249 lung adenocarcinoma Diseases 0.000 description 2
- 201000005243 lung squamous cell carcinoma Diseases 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 238000004949 mass spectrometry Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 229960004961 mechlorethamine Drugs 0.000 description 2
- HAWPXGHAZFHHAD-UHFFFAOYSA-N mechlorethamine Chemical compound ClCCN(C)CCCl HAWPXGHAZFHHAD-UHFFFAOYSA-N 0.000 description 2
- GLVAUDGFNGKCSF-UHFFFAOYSA-N mercaptopurine Chemical compound S=C1NC=NC2=C1NC=N2 GLVAUDGFNGKCSF-UHFFFAOYSA-N 0.000 description 2
- 208000021039 metastatic melanoma Diseases 0.000 description 2
- 229960001156 mitoxantrone Drugs 0.000 description 2
- KKZJGLLVHKMTCM-UHFFFAOYSA-N mitoxantrone Chemical compound O=C1C2=C(O)C=CC(O)=C2C(=O)C2=C1C(NCCNCCO)=CC=C2NCCNCCO KKZJGLLVHKMTCM-UHFFFAOYSA-N 0.000 description 2
- 238000011242 molecular targeted therapy Methods 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 238000013188 needle biopsy Methods 0.000 description 2
- 238000007481 next generation sequencing Methods 0.000 description 2
- 229960003301 nivolumab Drugs 0.000 description 2
- 239000002773 nucleotide Substances 0.000 description 2
- 125000003729 nucleotide group Chemical group 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 201000010302 ovarian serous cystadenocarcinoma Diseases 0.000 description 2
- 229960001592 paclitaxel Drugs 0.000 description 2
- 201000002094 pancreatic adenocarcinoma Diseases 0.000 description 2
- 229960001972 panitumumab Drugs 0.000 description 2
- 229960000639 pazopanib Drugs 0.000 description 2
- CUIHSIWYWATEQL-UHFFFAOYSA-N pazopanib Chemical compound C1=CC2=C(C)N(C)N=C2C=C1N(C)C(N=1)=CC=NC=1NC1=CC=C(C)C(S(N)(=O)=O)=C1 CUIHSIWYWATEQL-UHFFFAOYSA-N 0.000 description 2
- 229940121655 pd-1 inhibitor Drugs 0.000 description 2
- QOFFJEBXNKRSPX-ZDUSSCGKSA-N pemetrexed Chemical compound C1=N[C]2NC(N)=NC(=O)C2=C1CCC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 QOFFJEBXNKRSPX-ZDUSSCGKSA-N 0.000 description 2
- 229960005079 pemetrexed Drugs 0.000 description 2
- 108010056274 polo-like kinase 1 Proteins 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000003449 preventive effect Effects 0.000 description 2
- 238000004393 prognosis Methods 0.000 description 2
- 201000005825 prostate adenocarcinoma Diseases 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 102000016914 ras Proteins Human genes 0.000 description 2
- 201000001281 rectum adenocarcinoma Diseases 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000012340 reverse transcriptase PCR Methods 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000010187 selection method Methods 0.000 description 2
- 238000009097 single-agent therapy Methods 0.000 description 2
- 201000003708 skin melanoma Diseases 0.000 description 2
- 230000000391 smoking effect Effects 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 2
- 229940022511 therapeutic cancer vaccine Drugs 0.000 description 2
- 230000004797 therapeutic response Effects 0.000 description 2
- 201000002510 thyroid cancer Diseases 0.000 description 2
- 208000013077 thyroid gland carcinoma Diseases 0.000 description 2
- 238000012549 training Methods 0.000 description 2
- 229960004066 trametinib Drugs 0.000 description 2
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 2
- 238000012546 transfer Methods 0.000 description 2
- 229960001612 trastuzumab emtansine Drugs 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- 238000002604 ultrasonography Methods 0.000 description 2
- 241000701161 unidentified adenovirus Species 0.000 description 2
- 210000003932 urinary bladder Anatomy 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- 201000003701 uterine corpus endometrial carcinoma Diseases 0.000 description 2
- 108091044232 virus miR-BART9 stem-loop Proteins 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- 102100036537 von Willebrand factor Human genes 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 238000012049 whole transcriptome sequencing Methods 0.000 description 2
- STUWGJZDJHPWGZ-LBPRGKRZSA-N (2S)-N1-[4-methyl-5-[2-(1,1,1-trifluoro-2-methylpropan-2-yl)-4-pyridinyl]-2-thiazolyl]pyrrolidine-1,2-dicarboxamide Chemical compound S1C(C=2C=C(N=CC=2)C(C)(C)C(F)(F)F)=C(C)N=C1NC(=O)N1CCC[C@H]1C(N)=O STUWGJZDJHPWGZ-LBPRGKRZSA-N 0.000 description 1
- YOVVNQKCSKSHKT-HNNXBMFYSA-N (2s)-1-[4-[[2-(2-aminopyrimidin-5-yl)-7-methyl-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-hydroxypropan-1-one Chemical compound C1CN(C(=O)[C@@H](O)C)CCN1CC1=C(C)C2=NC(C=3C=NC(N)=NC=3)=NC(N3CCOCC3)=C2S1 YOVVNQKCSKSHKT-HNNXBMFYSA-N 0.000 description 1
- KCOYQXZDFIIGCY-CZIZESTLSA-N (3e)-4-amino-5-fluoro-3-[5-(4-methylpiperazin-1-yl)-1,3-dihydrobenzimidazol-2-ylidene]quinolin-2-one Chemical compound C1CN(C)CCN1C1=CC=C(N\C(N2)=C/3C(=C4C(F)=CC=CC4=NC\3=O)N)C2=C1 KCOYQXZDFIIGCY-CZIZESTLSA-N 0.000 description 1
- NYNZQNWKBKUAII-KBXCAEBGSA-N (3s)-n-[5-[(2r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl]pyrazolo[1,5-a]pyrimidin-3-yl]-3-hydroxypyrrolidine-1-carboxamide Chemical compound C1[C@@H](O)CCN1C(=O)NC1=C2N=C(N3[C@H](CCC3)C=3C(=CC=C(F)C=3)F)C=CN2N=C1 NYNZQNWKBKUAII-KBXCAEBGSA-N 0.000 description 1
- FPVKHBSQESCIEP-UHFFFAOYSA-N (8S)-3-(2-deoxy-beta-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepin-8-ol Natural products C1C(O)C(CO)OC1N1C(NC=NCC2O)=C2N=C1 FPVKHBSQESCIEP-UHFFFAOYSA-N 0.000 description 1
- FDKXTQMXEQVLRF-ZHACJKMWSA-N (E)-dacarbazine Chemical compound CN(C)\N=N\c1[nH]cnc1C(N)=O FDKXTQMXEQVLRF-ZHACJKMWSA-N 0.000 description 1
- SADXACCFNXBCFY-IYNHSRRRSA-N (e)-n-[4-[3-chloro-4-(pyridin-2-ylmethoxy)anilino]-3-cyano-7-ethoxyquinolin-6-yl]-3-[(2r)-1-methylpyrrolidin-2-yl]prop-2-enamide Chemical compound C=12C=C(NC(=O)\C=C\[C@@H]3N(CCC3)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 SADXACCFNXBCFY-IYNHSRRRSA-N 0.000 description 1
- DEVSOMFAQLZNKR-RJRFIUFISA-N (z)-3-[3-[3,5-bis(trifluoromethyl)phenyl]-1,2,4-triazol-1-yl]-n'-pyrazin-2-ylprop-2-enehydrazide Chemical compound FC(F)(F)C1=CC(C(F)(F)F)=CC(C2=NN(\C=C/C(=O)NNC=3N=CC=NC=3)C=N2)=C1 DEVSOMFAQLZNKR-RJRFIUFISA-N 0.000 description 1
- LPFWVDIFUFFKJU-UHFFFAOYSA-N 1-[4-[4-(3,4-dichloro-2-fluoroanilino)-7-methoxyquinazolin-6-yl]oxypiperidin-1-yl]prop-2-en-1-one Chemical compound C=12C=C(OC3CCN(CC3)C(=O)C=C)C(OC)=CC2=NC=NC=1NC1=CC=C(Cl)C(Cl)=C1F LPFWVDIFUFFKJU-UHFFFAOYSA-N 0.000 description 1
- BJHCYTJNPVGSBZ-YXSASFKJSA-N 1-[4-[6-amino-5-[(Z)-methoxyiminomethyl]pyrimidin-4-yl]oxy-2-chlorophenyl]-3-ethylurea Chemical compound CCNC(=O)Nc1ccc(Oc2ncnc(N)c2\C=N/OC)cc1Cl BJHCYTJNPVGSBZ-YXSASFKJSA-N 0.000 description 1
- KSMZEXLVHXZPEF-UHFFFAOYSA-N 1-[[4-[(4-fluoro-2-methyl-1h-indol-5-yl)oxy]-6-methoxyquinolin-7-yl]oxymethyl]cyclopropan-1-amine Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)C=CN=C2C=C1OCC1(N)CC1 KSMZEXLVHXZPEF-UHFFFAOYSA-N 0.000 description 1
- 108010058566 130-nm albumin-bound paclitaxel Proteins 0.000 description 1
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 description 1
- IUVCFHHAEHNCFT-INIZCTEOSA-N 2-[(1s)-1-[4-amino-3-(3-fluoro-4-propan-2-yloxyphenyl)pyrazolo[3,4-d]pyrimidin-1-yl]ethyl]-6-fluoro-3-(3-fluorophenyl)chromen-4-one Chemical compound C1=C(F)C(OC(C)C)=CC=C1C(C1=C(N)N=CN=C11)=NN1[C@@H](C)C1=C(C=2C=C(F)C=CC=2)C(=O)C2=CC(F)=CC=C2O1 IUVCFHHAEHNCFT-INIZCTEOSA-N 0.000 description 1
- LIOLIMKSCNQPLV-UHFFFAOYSA-N 2-fluoro-n-methyl-4-[7-(quinolin-6-ylmethyl)imidazo[1,2-b][1,2,4]triazin-2-yl]benzamide Chemical compound C1=C(F)C(C(=O)NC)=CC=C1C1=NN2C(CC=3C=C4C=CC=NC4=CC=3)=CN=C2N=C1 LIOLIMKSCNQPLV-UHFFFAOYSA-N 0.000 description 1
- BEUQXVWXFDOSAQ-UHFFFAOYSA-N 2-methyl-2-[4-[2-(5-methyl-2-propan-2-yl-1,2,4-triazol-3-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepin-9-yl]pyrazol-1-yl]propanamide Chemical compound CC(C)N1N=C(C)N=C1C1=CN(CCOC=2C3=CC=C(C=2)C2=CN(N=C2)C(C)(C)C(N)=O)C3=N1 BEUQXVWXFDOSAQ-UHFFFAOYSA-N 0.000 description 1
- XYDNMOZJKOGZLS-NSHDSACASA-N 3-[(1s)-1-imidazo[1,2-a]pyridin-6-ylethyl]-5-(1-methylpyrazol-4-yl)triazolo[4,5-b]pyrazine Chemical compound N1=C2N([C@H](C3=CN4C=CN=C4C=C3)C)N=NC2=NC=C1C=1C=NN(C)C=1 XYDNMOZJKOGZLS-NSHDSACASA-N 0.000 description 1
- JUSFANSTBFGBAF-IRXDYDNUSA-N 3-[2,4-bis[(3s)-3-methylmorpholin-4-yl]pyrido[2,3-d]pyrimidin-7-yl]-n-methylbenzamide Chemical compound CNC(=O)C1=CC=CC(C=2N=C3N=C(N=C(C3=CC=2)N2[C@H](COCC2)C)N2[C@H](COCC2)C)=C1 JUSFANSTBFGBAF-IRXDYDNUSA-N 0.000 description 1
- BGLPECHZZQDNCD-UHFFFAOYSA-N 4-(cyclopropylamino)-2-[4-(4-ethylsulfonylpiperazin-1-yl)anilino]pyrimidine-5-carboxamide Chemical compound C1CN(S(=O)(=O)CC)CCN1C(C=C1)=CC=C1NC1=NC=C(C(N)=O)C(NC2CC2)=N1 BGLPECHZZQDNCD-UHFFFAOYSA-N 0.000 description 1
- XXJWYDDUDKYVKI-UHFFFAOYSA-N 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[3-(1-pyrrolidinyl)propoxy]quinazoline Chemical compound COC1=CC2=C(OC=3C(=C4C=C(C)NC4=CC=3)F)N=CN=C2C=C1OCCCN1CCCC1 XXJWYDDUDKYVKI-UHFFFAOYSA-N 0.000 description 1
- TVTXCJFHQKSQQM-LJQIRTBHSA-N 4-[[(2r,3s,4r,5s)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoic acid Chemical compound COC1=CC(C(O)=O)=CC=C1NC(=O)[C@H]1[C@H](C=2C(=C(Cl)C=CC=2)F)[C@@](C#N)(C=2C(=CC(Cl)=CC=2)F)[C@H](CC(C)(C)C)N1 TVTXCJFHQKSQQM-LJQIRTBHSA-N 0.000 description 1
- ZLHFILGSQDJULK-UHFFFAOYSA-N 4-[[9-chloro-7-(2-fluoro-6-methoxyphenyl)-5H-pyrimido[5,4-d][2]benzazepin-2-yl]amino]-2-methoxybenzoic acid Chemical compound C1=C(C(O)=O)C(OC)=CC(NC=2N=C3C4=CC=C(Cl)C=C4C(=NCC3=CN=2)C=2C(=CC=CC=2F)OC)=C1 ZLHFILGSQDJULK-UHFFFAOYSA-N 0.000 description 1
- TVZGACDUOSZQKY-LBPRGKRZSA-N 4-aminofolic acid Chemical compound C1=NC2=NC(N)=NC(N)=C2N=C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 TVZGACDUOSZQKY-LBPRGKRZSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- UWXSAYUXVSFDBQ-CYBMUJFWSA-N 4-n-[3-chloro-4-(1,3-thiazol-2-ylmethoxy)phenyl]-6-n-[(4r)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]quinazoline-4,6-diamine Chemical compound C[C@@H]1COC(NC=2C=C3C(NC=4C=C(Cl)C(OCC=5SC=CN=5)=CC=4)=NC=NC3=CC=2)=N1 UWXSAYUXVSFDBQ-CYBMUJFWSA-N 0.000 description 1
- IDPUKCWIGUEADI-UHFFFAOYSA-N 5-[bis(2-chloroethyl)amino]uracil Chemical compound ClCCN(CCCl)C1=CNC(=O)NC1=O IDPUKCWIGUEADI-UHFFFAOYSA-N 0.000 description 1
- NMUSYJAQQFHJEW-KVTDHHQDSA-N 5-azacytidine Chemical compound O=C1N=C(N)N=CN1[C@H]1[C@H](O)[C@H](O)[C@@H](CO)O1 NMUSYJAQQFHJEW-KVTDHHQDSA-N 0.000 description 1
- AILRADAXUVEEIR-UHFFFAOYSA-N 5-chloro-4-n-(2-dimethylphosphorylphenyl)-2-n-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]pyrimidine-2,4-diamine Chemical compound COC1=CC(N2CCC(CC2)N2CCN(C)CC2)=CC=C1NC(N=1)=NC=C(Cl)C=1NC1=CC=CC=C1P(C)(C)=O AILRADAXUVEEIR-UHFFFAOYSA-N 0.000 description 1
- XSMSNFMDVXXHGJ-UHFFFAOYSA-N 6-(1h-indazol-6-yl)-n-(4-morpholin-4-ylphenyl)imidazo[1,2-a]pyrazin-8-amine Chemical compound C1COCCN1C(C=C1)=CC=C1NC1=NC(C=2C=C3NN=CC3=CC=2)=CN2C1=NC=C2 XSMSNFMDVXXHGJ-UHFFFAOYSA-N 0.000 description 1
- WYWHKKSPHMUBEB-UHFFFAOYSA-N 6-Mercaptoguanine Natural products N1C(N)=NC(=S)C2=C1N=CN2 WYWHKKSPHMUBEB-UHFFFAOYSA-N 0.000 description 1
- FJHBVJOVLFPMQE-QFIPXVFZSA-N 7-Ethyl-10-Hydroxy-Camptothecin Chemical compound C1=C(O)C=C2C(CC)=C(CN3C(C4=C([C@@](C(=O)OC4)(O)CC)C=C33)=O)C3=NC2=C1 FJHBVJOVLFPMQE-QFIPXVFZSA-N 0.000 description 1
- RHXHGRAEPCAFML-UHFFFAOYSA-N 7-cyclopentyl-n,n-dimethyl-2-[(5-piperazin-1-ylpyridin-2-yl)amino]pyrrolo[2,3-d]pyrimidine-6-carboxamide Chemical compound N1=C2N(C3CCCC3)C(C(=O)N(C)C)=CC2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 RHXHGRAEPCAFML-UHFFFAOYSA-N 0.000 description 1
- SJVQHLPISAIATJ-ZDUSSCGKSA-N 8-chloro-2-phenyl-3-[(1S)-1-(7H-purin-6-ylamino)ethyl]-1-isoquinolinone Chemical compound C1([C@@H](NC=2C=3N=CNC=3N=CN=2)C)=CC2=CC=CC(Cl)=C2C(=O)N1C1=CC=CC=C1 SJVQHLPISAIATJ-ZDUSSCGKSA-N 0.000 description 1
- BUROJSBIWGDYCN-GAUTUEMISA-N AP 23573 Chemical compound C1C[C@@H](OP(C)(C)=O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 BUROJSBIWGDYCN-GAUTUEMISA-N 0.000 description 1
- GBJVVSCPOBPEIT-UHFFFAOYSA-N AZT-1152 Chemical compound N=1C=NC2=CC(OCCCN(CC)CCOP(O)(O)=O)=CC=C2C=1NC(=NN1)C=C1CC(=O)NC1=CC=CC(F)=C1 GBJVVSCPOBPEIT-UHFFFAOYSA-N 0.000 description 1
- 102100027211 Albumin Human genes 0.000 description 1
- 241000710929 Alphavirus Species 0.000 description 1
- 229940124618 Anlotinib Drugs 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 108091023037 Aptamer Proteins 0.000 description 1
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 description 1
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 description 1
- MLDQJTXFUGDVEO-UHFFFAOYSA-N BAY-43-9006 Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=CC(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 MLDQJTXFUGDVEO-UHFFFAOYSA-N 0.000 description 1
- CWHUFRVAEUJCEF-UHFFFAOYSA-N BKM120 Chemical compound C1=NC(N)=CC(C(F)(F)F)=C1C1=CC(N2CCOCC2)=NC(N2CCOCC2)=N1 CWHUFRVAEUJCEF-UHFFFAOYSA-N 0.000 description 1
- 102100026189 Beta-galactosidase Human genes 0.000 description 1
- 206010005003 Bladder cancer Diseases 0.000 description 1
- 108010006654 Bleomycin Proteins 0.000 description 1
- 208000003174 Brain Neoplasms Diseases 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 206010006223 Breast discharge Diseases 0.000 description 1
- 206010006272 Breast mass Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- 102100036166 C-X-C chemokine receptor type 1 Human genes 0.000 description 1
- 125000001433 C-terminal amino-acid group Chemical group 0.000 description 1
- LXFOLMYKSYSZQS-LURJZOHASA-N CC(C)N(C[C@H]1O[C@H]([C@H](O)[C@@H]1O)n1cnc2c(N)ncnc12)[C@@H]1C[C@H](CCc2nc3cc(ccc3[nH]2)C(C)(C)C)C1 Chemical compound CC(C)N(C[C@H]1O[C@H]([C@H](O)[C@@H]1O)n1cnc2c(N)ncnc12)[C@@H]1C[C@H](CCc2nc3cc(ccc3[nH]2)C(C)(C)C)C1 LXFOLMYKSYSZQS-LURJZOHASA-N 0.000 description 1
- 239000012275 CTLA-4 inhibitor Substances 0.000 description 1
- FVLVBPDQNARYJU-XAHDHGMMSA-N C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O Chemical compound C[C@H]1CCC(CC1)NC(=O)N(CCCl)N=O FVLVBPDQNARYJU-XAHDHGMMSA-N 0.000 description 1
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- SHHKQEUPHAENFK-UHFFFAOYSA-N Carboquone Chemical compound O=C1C(C)=C(N2CC2)C(=O)C(C(COC(N)=O)OC)=C1N1CC1 SHHKQEUPHAENFK-UHFFFAOYSA-N 0.000 description 1
- AOCCBINRVIKJHY-UHFFFAOYSA-N Carmofur Chemical compound CCCCCCNC(=O)N1C=C(F)C(=O)NC1=O AOCCBINRVIKJHY-UHFFFAOYSA-N 0.000 description 1
- DLGOEMSEDOSKAD-UHFFFAOYSA-N Carmustine Chemical compound ClCCNC(=O)N(N=O)CCCl DLGOEMSEDOSKAD-UHFFFAOYSA-N 0.000 description 1
- PTOAARAWEBMLNO-KVQBGUIXSA-N Cladribine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)O1 PTOAARAWEBMLNO-KVQBGUIXSA-N 0.000 description 1
- 108091026890 Coding region Proteins 0.000 description 1
- 102100033781 Collagen alpha-2(IV) chain Human genes 0.000 description 1
- 102100033780 Collagen alpha-3(IV) chain Human genes 0.000 description 1
- 102100033779 Collagen alpha-4(IV) chain Human genes 0.000 description 1
- 102100033775 Collagen alpha-5(IV) chain Human genes 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- 208000001333 Colorectal Neoplasms Diseases 0.000 description 1
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 1
- UHDGCWIWMRVCDJ-CCXZUQQUSA-N Cytarabine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](O)[C@H](O)[C@@H](CO)O1 UHDGCWIWMRVCDJ-CCXZUQQUSA-N 0.000 description 1
- 229940123780 DNA topoisomerase I inhibitor Drugs 0.000 description 1
- 108010092160 Dactinomycin Proteins 0.000 description 1
- ZBNZXTGUTAYRHI-UHFFFAOYSA-N Dasatinib Chemical compound C=1C(N2CCN(CCO)CC2)=NC(C)=NC=1NC(S1)=NC=C1C(=O)NC1=C(C)C=CC=C1Cl ZBNZXTGUTAYRHI-UHFFFAOYSA-N 0.000 description 1
- 241000702421 Dependoparvovirus Species 0.000 description 1
- MWWSFMDVAYGXBV-RUELKSSGSA-N Doxorubicin hydrochloride Chemical compound Cl.O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 MWWSFMDVAYGXBV-RUELKSSGSA-N 0.000 description 1
- CUDVHEFYRIWYQD-UHFFFAOYSA-N E-3810 free base Chemical compound C=1C=C2C(C(=O)NC)=CC=CC2=CC=1OC(C1=CC=2OC)=CC=NC1=CC=2OCC1(N)CC1 CUDVHEFYRIWYQD-UHFFFAOYSA-N 0.000 description 1
- 206010066919 Epidemic polyarthritis Diseases 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- HKVAMNSJSFKALM-GKUWKFKPSA-N Everolimus Chemical compound C1C[C@@H](OCCO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 HKVAMNSJSFKALM-GKUWKFKPSA-N 0.000 description 1
- 108010008177 Fd immunoglobulins Proteins 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010064571 Gene mutation Diseases 0.000 description 1
- 208000034826 Genetic Predisposition to Disease Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 208000029433 Herpesviridae infectious disease Diseases 0.000 description 1
- 101000952099 Homo sapiens Antiviral innate immune response receptor RIG-I Proteins 0.000 description 1
- 101000947174 Homo sapiens C-X-C chemokine receptor type 1 Proteins 0.000 description 1
- 101000710876 Homo sapiens Collagen alpha-2(IV) chain Proteins 0.000 description 1
- 101000710873 Homo sapiens Collagen alpha-3(IV) chain Proteins 0.000 description 1
- 101000710870 Homo sapiens Collagen alpha-4(IV) chain Proteins 0.000 description 1
- 101000710886 Homo sapiens Collagen alpha-5(IV) chain Proteins 0.000 description 1
- 101001005719 Homo sapiens Melanoma-associated antigen 3 Proteins 0.000 description 1
- XDXDZDZNSLXDNA-TZNDIEGXSA-N Idarubicin Chemical compound C1[C@H](N)[C@H](O)[C@H](C)O[C@H]1O[C@@H]1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2C[C@@](O)(C(C)=O)C1 XDXDZDZNSLXDNA-TZNDIEGXSA-N 0.000 description 1
- XDXDZDZNSLXDNA-UHFFFAOYSA-N Idarubicin Natural products C1C(N)C(O)C(C)OC1OC1C2=C(O)C(C(=O)C3=CC=CC=C3C3=O)=C3C(O)=C2CC(O)(C(C)=O)C1 XDXDZDZNSLXDNA-UHFFFAOYSA-N 0.000 description 1
- 229940076838 Immune checkpoint inhibitor Drugs 0.000 description 1
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 1
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 1
- 108091008026 Inhibitory immune checkpoint proteins Proteins 0.000 description 1
- 102000037984 Inhibitory immune checkpoint proteins Human genes 0.000 description 1
- 108010047761 Interferon-alpha Proteins 0.000 description 1
- 102000006992 Interferon-alpha Human genes 0.000 description 1
- 102000001702 Intracellular Signaling Peptides and Proteins Human genes 0.000 description 1
- 108010068964 Intracellular Signaling Peptides and Proteins Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- FBOZXECLQNJBKD-ZDUSSCGKSA-N L-methotrexate Chemical compound C=1N=C2N=C(N)N=C(N)C2=NC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 FBOZXECLQNJBKD-ZDUSSCGKSA-N 0.000 description 1
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 1
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 1
- 239000005511 L01XE05 - Sorafenib Substances 0.000 description 1
- 239000002067 L01XE06 - Dasatinib Substances 0.000 description 1
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 1
- 239000005536 L01XE08 - Nilotinib Substances 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 239000002145 L01XE14 - Bosutinib Substances 0.000 description 1
- 239000002146 L01XE16 - Crizotinib Substances 0.000 description 1
- 239000002144 L01XE18 - Ruxolitinib Substances 0.000 description 1
- 239000002138 L01XE21 - Regorafenib Substances 0.000 description 1
- 239000002139 L01XE22 - Masitinib Substances 0.000 description 1
- 239000002137 L01XE24 - Ponatinib Substances 0.000 description 1
- 239000002176 L01XE26 - Cabozantinib Substances 0.000 description 1
- 239000002177 L01XE27 - Ibrutinib Substances 0.000 description 1
- UCEQXRCJXIVODC-PMACEKPBSA-N LSM-1131 Chemical compound C1CCC2=CC=CC3=C2N1C=C3[C@@H]1C(=O)NC(=O)[C@H]1C1=CNC2=CC=CC=C12 UCEQXRCJXIVODC-PMACEKPBSA-N 0.000 description 1
- UIARLYUEJFELEN-LROUJFHJSA-N LSM-1231 Chemical compound C12=C3N4C5=CC=CC=C5C3=C3C(=O)NCC3=C2C2=CC=CC=C2N1[C@]1(C)[C@](CO)(O)C[C@H]4O1 UIARLYUEJFELEN-LROUJFHJSA-N 0.000 description 1
- GQYIWUVLTXOXAJ-UHFFFAOYSA-N Lomustine Chemical compound ClCCN(N=O)C(=O)NC1CCCCC1 GQYIWUVLTXOXAJ-UHFFFAOYSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 102100025082 Melanoma-associated antigen 3 Human genes 0.000 description 1
- VFKZTMPDYBFSTM-KVTDHHQDSA-N Mitobronitol Chemical compound BrC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CBr VFKZTMPDYBFSTM-KVTDHHQDSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 1
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 description 1
- CXQHYVUVSFXTMY-UHFFFAOYSA-N N1'-[3-fluoro-4-[[6-methoxy-7-[3-(4-morpholinyl)propoxy]-4-quinolinyl]oxy]phenyl]-N1-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide Chemical compound C1=CN=C2C=C(OCCCN3CCOCC3)C(OC)=CC2=C1OC(C(=C1)F)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 CXQHYVUVSFXTMY-UHFFFAOYSA-N 0.000 description 1
- 241000208125 Nicotiana Species 0.000 description 1
- 235000002637 Nicotiana tabacum Nutrition 0.000 description 1
- 238000000636 Northern blotting Methods 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 206010033307 Overweight Diseases 0.000 description 1
- 239000012271 PD-L1 inhibitor Substances 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 1
- 208000005228 Pericardial Effusion Diseases 0.000 description 1
- KMSKQZKKOZQFFG-HSUXVGOQSA-N Pirarubicin Chemical compound O([C@H]1[C@@H](N)C[C@@H](O[C@H]1C)O[C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1CCCCO1 KMSKQZKKOZQFFG-HSUXVGOQSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- HFVNWDWLWUCIHC-GUPDPFMOSA-N Prednimustine Chemical compound O=C([C@@]1(O)CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)[C@@H](O)C[C@@]21C)COC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 HFVNWDWLWUCIHC-GUPDPFMOSA-N 0.000 description 1
- 108010026552 Proteome Proteins 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 238000011529 RT qPCR Methods 0.000 description 1
- AHHFEZNOXOZZQA-ZEBDFXRSSA-N Ranimustine Chemical compound CO[C@H]1O[C@H](CNC(=O)N(CCCl)N=O)[C@@H](O)[C@H](O)[C@H]1O AHHFEZNOXOZZQA-ZEBDFXRSSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010038389 Renal cancer Diseases 0.000 description 1
- 108700008625 Reporter Genes Proteins 0.000 description 1
- 241000710942 Ross River virus Species 0.000 description 1
- 190014017285 Satraplatin Chemical compound 0.000 description 1
- 241000710961 Semliki Forest virus Species 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- 241000710960 Sindbis virus Species 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 238000012167 Small RNA sequencing Methods 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- 108091027544 Subgenomic mRNA Proteins 0.000 description 1
- QJJXYPPXXYFBGM-LFZNUXCKSA-N Tacrolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1\C=C(/C)[C@@H]1[C@H](C)[C@@H](O)CC(=O)[C@H](CC=C)/C=C(C)/C[C@H](C)C[C@H](OC)[C@H]([C@H](C[C@H]2C)OC)O[C@@]2(O)C(=O)C(=O)N2CCCC[C@H]2C(=O)O1 QJJXYPPXXYFBGM-LFZNUXCKSA-N 0.000 description 1
- BPEGJWRSRHCHSN-UHFFFAOYSA-N Temozolomide Chemical compound O=C1N(C)N=NC2=C(C(N)=O)N=CN21 BPEGJWRSRHCHSN-UHFFFAOYSA-N 0.000 description 1
- CBPNZQVSJQDFBE-FUXHJELOSA-N Temsirolimus Chemical compound C1C[C@@H](OC(=O)C(C)(CO)CO)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 CBPNZQVSJQDFBE-FUXHJELOSA-N 0.000 description 1
- FOCVUCIESVLUNU-UHFFFAOYSA-N Thiotepa Chemical compound C1CN1P(N1CC1)(=S)N1CC1 FOCVUCIESVLUNU-UHFFFAOYSA-N 0.000 description 1
- 239000004012 Tofacitinib Substances 0.000 description 1
- IVTVGDXNLFLDRM-HNNXBMFYSA-N Tomudex Chemical compound C=1C=C2NC(C)=NC(=O)C2=CC=1CN(C)C1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)S1 IVTVGDXNLFLDRM-HNNXBMFYSA-N 0.000 description 1
- 101710183280 Topoisomerase Proteins 0.000 description 1
- 239000000365 Topoisomerase I Inhibitor Substances 0.000 description 1
- YCPOZVAOBBQLRI-WDSKDSINSA-N Treosulfan Chemical compound CS(=O)(=O)OC[C@H](O)[C@@H](O)COS(C)(=O)=O YCPOZVAOBBQLRI-WDSKDSINSA-N 0.000 description 1
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 1
- 241000710959 Venezuelan equine encephalitis virus Species 0.000 description 1
- 208000036142 Viral infection Diseases 0.000 description 1
- XSMVECZRZBFTIZ-UHFFFAOYSA-M [2-(aminomethyl)cyclobutyl]methanamine;2-oxidopropanoate;platinum(4+) Chemical compound [Pt+4].CC([O-])C([O-])=O.NCC1CCC1CN XSMVECZRZBFTIZ-UHFFFAOYSA-M 0.000 description 1
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 1
- FWHKHRVHKXYOFT-UHFFFAOYSA-M [5-(1,3,2-dioxaphosphinan-2-yloxy)-6-oxocyclohexa-1,3-dien-1-yl]-trimethylazanium;iodide Chemical compound [I-].O=C1C([N+](C)(C)C)=CC=CC1OP1OCCCO1 FWHKHRVHKXYOFT-UHFFFAOYSA-M 0.000 description 1
- 229950001573 abemaciclib Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 229950009821 acalabrutinib Drugs 0.000 description 1
- WDENQIQQYWYTPO-IBGZPJMESA-N acalabrutinib Chemical compound CC#CC(=O)N1CCC[C@H]1C1=NC(C=2C=CC(=CC=2)C(=O)NC=2N=CC=CC=2)=C2N1C=CN=C2N WDENQIQQYWYTPO-IBGZPJMESA-N 0.000 description 1
- USZYSDMBJDPRIF-SVEJIMAYSA-N aclacinomycin A Chemical compound O([C@H]1[C@@H](O)C[C@@H](O[C@H]1C)O[C@H]1[C@H](C[C@@H](O[C@H]1C)O[C@H]1C[C@]([C@@H](C2=CC=3C(=O)C4=CC=CC(O)=C4C(=O)C=3C(O)=C21)C(=O)OC)(O)CC)N(C)C)[C@H]1CCC(=O)[C@H](C)O1 USZYSDMBJDPRIF-SVEJIMAYSA-N 0.000 description 1
- 229960004176 aclarubicin Drugs 0.000 description 1
- 229930183665 actinomycin Natural products 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960001686 afatinib Drugs 0.000 description 1
- ULXXDDBFHOBEHA-CWDCEQMOSA-N afatinib Chemical compound N1=CN=C2C=C(O[C@@H]3COCC3)C(NC(=O)/C=C/CN(C)C)=CC2=C1NC1=CC=C(F)C(Cl)=C1 ULXXDDBFHOBEHA-CWDCEQMOSA-N 0.000 description 1
- 229960001611 alectinib Drugs 0.000 description 1
- KDGFLJKFZUIJMX-UHFFFAOYSA-N alectinib Chemical compound CCC1=CC=2C(=O)C(C3=CC=C(C=C3N3)C#N)=C3C(C)(C)C=2C=C1N(CC1)CCC1N1CCOCC1 KDGFLJKFZUIJMX-UHFFFAOYSA-N 0.000 description 1
- 229960000548 alemtuzumab Drugs 0.000 description 1
- 229950009447 alisertib Drugs 0.000 description 1
- 229940100198 alkylating agent Drugs 0.000 description 1
- 239000002168 alkylating agent Substances 0.000 description 1
- 229950010482 alpelisib Drugs 0.000 description 1
- 229960000473 altretamine Drugs 0.000 description 1
- 229950010817 alvocidib Drugs 0.000 description 1
- BIIVYFLTOXDAOV-YVEFUNNKSA-N alvocidib Chemical compound O[C@@H]1CN(C)CC[C@@H]1C1=C(O)C=C(O)C2=C1OC(C=1C(=CC=CC=1)Cl)=CC2=O BIIVYFLTOXDAOV-YVEFUNNKSA-N 0.000 description 1
- 229960003896 aminopterin Drugs 0.000 description 1
- 229960002550 amrubicin Drugs 0.000 description 1
- VJZITPJGSQKZMX-XDPRQOKASA-N amrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC=C4C(=O)C=3C(O)=C21)(N)C(=O)C)[C@H]1C[C@H](O)[C@H](O)CO1 VJZITPJGSQKZMX-XDPRQOKASA-N 0.000 description 1
- 229960001220 amsacrine Drugs 0.000 description 1
- XCPGHVQEEXUHNC-UHFFFAOYSA-N amsacrine Chemical compound COC1=CC(NS(C)(=O)=O)=CC=C1NC1=C(C=CC=C2)C2=NC2=CC=CC=C12 XCPGHVQEEXUHNC-UHFFFAOYSA-N 0.000 description 1
- 208000007502 anemia Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- RGHILYZRVFRRNK-UHFFFAOYSA-N anthracene-1,2-dione Chemical class C1=CC=C2C=C(C(C(=O)C=C3)=O)C3=CC2=C1 RGHILYZRVFRRNK-UHFFFAOYSA-N 0.000 description 1
- 229940045799 anthracyclines and related substance Drugs 0.000 description 1
- 230000000340 anti-metabolite Effects 0.000 description 1
- 230000000692 anti-sense effect Effects 0.000 description 1
- 229940100197 antimetabolite Drugs 0.000 description 1
- 239000002256 antimetabolite Substances 0.000 description 1
- 229940045719 antineoplastic alkylating agent nitrosoureas Drugs 0.000 description 1
- 230000005975 antitumor immune response Effects 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 229960003982 apatinib Drugs 0.000 description 1
- 229950004111 apitolisib Drugs 0.000 description 1
- 229950008049 apricoxib Drugs 0.000 description 1
- JTMITOKKUMVWRT-UHFFFAOYSA-N apricoxib Chemical compound C1=CC(OCC)=CC=C1C1=CC(C)=CN1C1=CC=C(S(N)(=O)=O)C=C1 JTMITOKKUMVWRT-UHFFFAOYSA-N 0.000 description 1
- 210000003567 ascitic fluid Anatomy 0.000 description 1
- 238000002820 assay format Methods 0.000 description 1
- 229960003852 atezolizumab Drugs 0.000 description 1
- 229960005370 atorvastatin Drugs 0.000 description 1
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 description 1
- 229960005207 auranofin Drugs 0.000 description 1
- 229940120638 avastin Drugs 0.000 description 1
- 229960003005 axitinib Drugs 0.000 description 1
- RITAVMQDGBJQJZ-FMIVXFBMSA-N axitinib Chemical compound CNC(=O)C1=CC=CC=C1SC1=CC=C(C(\C=C\C=2N=CC=CC=2)=NN2)C2=C1 RITAVMQDGBJQJZ-FMIVXFBMSA-N 0.000 description 1
- 229960002756 azacitidine Drugs 0.000 description 1
- KLNFSAOEKUDMFA-UHFFFAOYSA-N azanide;2-hydroxyacetic acid;platinum(2+) Chemical compound [NH2-].[NH2-].[Pt+2].OCC(O)=O KLNFSAOEKUDMFA-UHFFFAOYSA-N 0.000 description 1
- 150000001541 aziridines Chemical class 0.000 description 1
- 229950005645 barasertib Drugs 0.000 description 1
- LNHWXBUNXOXMRL-VWLOTQADSA-N belotecan Chemical compound C1=CC=C2C(CCNC(C)C)=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 LNHWXBUNXOXMRL-VWLOTQADSA-N 0.000 description 1
- 229950011276 belotecan Drugs 0.000 description 1
- 229960002707 bendamustine Drugs 0.000 description 1
- YTKUWDBFDASYHO-UHFFFAOYSA-N bendamustine Chemical compound ClCCN(CCCl)C1=CC=C2N(C)C(CCCC(O)=O)=NC2=C1 YTKUWDBFDASYHO-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 108010005774 beta-Galactosidase Proteins 0.000 description 1
- 210000003445 biliary tract Anatomy 0.000 description 1
- 229910002056 binary alloy Inorganic materials 0.000 description 1
- 229950003054 binimetinib Drugs 0.000 description 1
- ACWZRVQXLIRSDF-UHFFFAOYSA-N binimetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1F ACWZRVQXLIRSDF-UHFFFAOYSA-N 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 230000008236 biological pathway Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 229960001561 bleomycin Drugs 0.000 description 1
- OYVAGSVQBOHSSS-UAPAGMARSA-O bleomycin A2 Chemical compound N([C@H](C(=O)N[C@H](C)[C@@H](O)[C@H](C)C(=O)N[C@@H]([C@H](O)C)C(=O)NCCC=1SC=C(N=1)C=1SC=C(N=1)C(=O)NCCC[S+](C)C)[C@@H](O[C@H]1[C@H]([C@@H](O)[C@H](O)[C@H](CO)O1)O[C@@H]1[C@H]([C@@H](OC(N)=O)[C@H](O)[C@@H](CO)O1)O)C=1N=CNC=1)C(=O)C1=NC([C@H](CC(N)=O)NC[C@H](N)C(N)=O)=NC(N)=C1C OYVAGSVQBOHSSS-UAPAGMARSA-O 0.000 description 1
- 229960003008 blinatumomab Drugs 0.000 description 1
- 229940101815 blincyto Drugs 0.000 description 1
- 229960003736 bosutinib Drugs 0.000 description 1
- UBPYILGKFZZVDX-UHFFFAOYSA-N bosutinib Chemical compound C1=C(Cl)C(OC)=CC(NC=2C3=CC(OC)=C(OCCCN4CCN(C)CC4)C=C3N=CC=2C#N)=C1Cl UBPYILGKFZZVDX-UHFFFAOYSA-N 0.000 description 1
- 238000002725 brachytherapy Methods 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 229950004272 brigatinib Drugs 0.000 description 1
- 229950001478 brontictuzumab Drugs 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229950003628 buparlisib Drugs 0.000 description 1
- 229960002092 busulfan Drugs 0.000 description 1
- 229960001292 cabozantinib Drugs 0.000 description 1
- ONIQOQHATWINJY-UHFFFAOYSA-N cabozantinib Chemical compound C=12C=C(OC)C(OC)=CC2=NC=CC=1OC(C=C1)=CC=C1NC(=O)C1(C(=O)NC=2C=CC(F)=CC=2)CC1 ONIQOQHATWINJY-UHFFFAOYSA-N 0.000 description 1
- 229940112129 campath Drugs 0.000 description 1
- 229940127093 camptothecin Drugs 0.000 description 1
- VSJKWCGYPAHWDS-FQEVSTJZSA-N camptothecin Chemical compound C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-FQEVSTJZSA-N 0.000 description 1
- 229950005852 capmatinib Drugs 0.000 description 1
- 229960002115 carboquone Drugs 0.000 description 1
- 229960003261 carmofur Drugs 0.000 description 1
- 229960005243 carmustine Drugs 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229960002412 cediranib Drugs 0.000 description 1
- 229960000590 celecoxib Drugs 0.000 description 1
- RZEKVGVHFLEQIL-UHFFFAOYSA-N celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 229950006295 cerdulatinib Drugs 0.000 description 1
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 1
- 229960005395 cetuximab Drugs 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 230000005591 charge neutralization Effects 0.000 description 1
- 229960004630 chlorambucil Drugs 0.000 description 1
- JCKYGMPEJWAADB-UHFFFAOYSA-N chlorambucil Chemical compound OC(=O)CCCC1=CC=C(N(CCCl)CCCl)C=C1 JCKYGMPEJWAADB-UHFFFAOYSA-N 0.000 description 1
- 239000003593 chromogenic compound Substances 0.000 description 1
- 229960002436 cladribine Drugs 0.000 description 1
- WDDPHFBMKLOVOX-AYQXTPAHSA-N clofarabine Chemical compound C1=NC=2C(N)=NC(Cl)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@@H]1F WDDPHFBMKLOVOX-AYQXTPAHSA-N 0.000 description 1
- 229960000928 clofarabine Drugs 0.000 description 1
- 229960002271 cobimetinib Drugs 0.000 description 1
- RESIMIUSNACMNW-BXRWSSRYSA-N cobimetinib fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F.C1C(O)([C@H]2NCCCC2)CN1C(=O)C1=CC=C(F)C(F)=C1NC1=CC=C(I)C=C1F RESIMIUSNACMNW-BXRWSSRYSA-N 0.000 description 1
- 230000001149 cognitive effect Effects 0.000 description 1
- 230000001427 coherent effect Effects 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 238000002591 computed tomography Methods 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 229950002550 copanlisib Drugs 0.000 description 1
- PZBCKZWLPGJMAO-UHFFFAOYSA-N copanlisib Chemical compound C1=CC=2C3=NCCN3C(NC(=O)C=3C=NC(N)=NC=3)=NC=2C(OC)=C1OCCCN1CCOCC1 PZBCKZWLPGJMAO-UHFFFAOYSA-N 0.000 description 1
- 229950009240 crenolanib Drugs 0.000 description 1
- DYNHJHQFHQTFTP-UHFFFAOYSA-N crenolanib Chemical compound C=1C=C2N(C=3N=C4C(N5CCC(N)CC5)=CC=CC4=CC=3)C=NC2=CC=1OCC1(C)COC1 DYNHJHQFHQTFTP-UHFFFAOYSA-N 0.000 description 1
- 229960005061 crizotinib Drugs 0.000 description 1
- KTEIFNKAUNYNJU-GFCCVEGCSA-N crizotinib Chemical compound O([C@H](C)C=1C(=C(F)C=CC=1Cl)Cl)C(C(=NC=1)N)=CC=1C(=C1)C=NN1C1CCNCC1 KTEIFNKAUNYNJU-GFCCVEGCSA-N 0.000 description 1
- 238000011498 curative surgery Methods 0.000 description 1
- PZAQDVNYNJBUTM-UHFFFAOYSA-L cyclohexane-1,2-diamine;7,7-dimethyloctanoate;platinum(2+) Chemical compound [Pt+2].NC1CCCCC1N.CC(C)(C)CCCCCC([O-])=O.CC(C)(C)CCCCCC([O-])=O PZAQDVNYNJBUTM-UHFFFAOYSA-L 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 229960000684 cytarabine Drugs 0.000 description 1
- 238000004163 cytometry Methods 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 239000003145 cytotoxic factor Substances 0.000 description 1
- 229960003901 dacarbazine Drugs 0.000 description 1
- LVXJQMNHJWSHET-AATRIKPKSA-N dacomitinib Chemical compound C=12C=C(NC(=O)\C=C\CN3CCCCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 LVXJQMNHJWSHET-AATRIKPKSA-N 0.000 description 1
- 229950002205 dacomitinib Drugs 0.000 description 1
- 229950006418 dactolisib Drugs 0.000 description 1
- JOGKUKXHTYWRGZ-UHFFFAOYSA-N dactolisib Chemical compound O=C1N(C)C2=CN=C3C=CC(C=4C=C5C=CC=CC5=NC=4)=CC3=C2N1C1=CC=C(C(C)(C)C#N)C=C1 JOGKUKXHTYWRGZ-UHFFFAOYSA-N 0.000 description 1
- 229960002448 dasatinib Drugs 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 208000028659 discharge Diseases 0.000 description 1
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 1
- 229960003668 docetaxel Drugs 0.000 description 1
- 229950005778 dovitinib Drugs 0.000 description 1
- 229960002918 doxorubicin hydrochloride Drugs 0.000 description 1
- 229950004949 duvelisib Drugs 0.000 description 1
- 238000010894 electron beam technology Methods 0.000 description 1
- 229950010133 enasidenib Drugs 0.000 description 1
- DYLUUSLLRIQKOE-UHFFFAOYSA-N enasidenib Chemical compound N=1C(C=2N=C(C=CC=2)C(F)(F)F)=NC(NCC(C)(O)C)=NC=1NC1=CC=NC(C(F)(F)F)=C1 DYLUUSLLRIQKOE-UHFFFAOYSA-N 0.000 description 1
- 229950001969 encorafenib Drugs 0.000 description 1
- 238000001861 endoscopic biopsy Methods 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 229950004136 entospletinib Drugs 0.000 description 1
- 229950000521 entrectinib Drugs 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 210000000981 epithelium Anatomy 0.000 description 1
- 229940082789 erbitux Drugs 0.000 description 1
- 229950004444 erdafitinib Drugs 0.000 description 1
- 229960001433 erlotinib Drugs 0.000 description 1
- AAKJLRGGTJKAMG-UHFFFAOYSA-N erlotinib Chemical compound C=12C=C(OCCOC)C(OCCOC)=CC2=NC=NC=1NC1=CC=CC(C#C)=C1 AAKJLRGGTJKAMG-UHFFFAOYSA-N 0.000 description 1
- 229960001842 estramustine Drugs 0.000 description 1
- FRPJXPJMRWBBIH-RBRWEJTLSA-N estramustine Chemical compound ClCCN(CCCl)C(=O)OC1=CC=C2[C@H]3CC[C@](C)([C@H](CC4)O)[C@@H]4[C@@H]3CCC2=C1 FRPJXPJMRWBBIH-RBRWEJTLSA-N 0.000 description 1
- 229940116333 ethyl lactate Drugs 0.000 description 1
- VJJPUSNTGOMMGY-MRVIYFEKSA-N etoposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@H](C)OC[C@H]4O3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 VJJPUSNTGOMMGY-MRVIYFEKSA-N 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 229960005167 everolimus Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 229960000961 floxuridine Drugs 0.000 description 1
- ODKNJVUHOIMIIZ-RRKCRQDMSA-N floxuridine Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(F)=C1 ODKNJVUHOIMIIZ-RRKCRQDMSA-N 0.000 description 1
- 229960000390 fludarabine Drugs 0.000 description 1
- GIUYCYHIANZCFB-FJFJXFQQSA-N fludarabine phosphate Chemical compound C1=NC=2C(N)=NC(F)=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@@H]1O GIUYCYHIANZCFB-FJFJXFQQSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 201000003444 follicular lymphoma Diseases 0.000 description 1
- 229950008692 foretinib Drugs 0.000 description 1
- 229950005309 fostamatinib Drugs 0.000 description 1
- GKDRMWXFWHEQQT-UHFFFAOYSA-N fostamatinib Chemical compound COC1=C(OC)C(OC)=CC(NC=2N=C(NC=3N=C4N(COP(O)(O)=O)C(=O)C(C)(C)OC4=CC=3)C(F)=CN=2)=C1 GKDRMWXFWHEQQT-UHFFFAOYSA-N 0.000 description 1
- 229960004783 fotemustine Drugs 0.000 description 1
- YAKWPXVTIGTRJH-UHFFFAOYSA-N fotemustine Chemical compound CCOP(=O)(OCC)C(C)NC(=O)N(CCCl)N=O YAKWPXVTIGTRJH-UHFFFAOYSA-N 0.000 description 1
- 238000007672 fourth generation sequencing Methods 0.000 description 1
- 229960002584 gefitinib Drugs 0.000 description 1
- XGALLCVXEZPNRQ-UHFFFAOYSA-N gefitinib Chemical compound C=12C=C(OCCCN3CCOCC3)C(OC)=CC2=NC=NC=1NC1=CC=C(F)C(Cl)=C1 XGALLCVXEZPNRQ-UHFFFAOYSA-N 0.000 description 1
- 230000004545 gene duplication Effects 0.000 description 1
- 238000003205 genotyping method Methods 0.000 description 1
- 229950006304 gilteritinib Drugs 0.000 description 1
- GYQYAJJFPNQOOW-UHFFFAOYSA-N gilteritinib Chemical compound N1=C(NC2CCOCC2)C(CC)=NC(C(N)=O)=C1NC(C=C1OC)=CC=C1N(CC1)CCC1N1CCN(C)CC1 GYQYAJJFPNQOOW-UHFFFAOYSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000012010 growth Effects 0.000 description 1
- 229940022353 herceptin Drugs 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- UUVWYPNAQBNQJQ-UHFFFAOYSA-N hexamethylmelamine Chemical compound CN(C)C1=NC(N(C)C)=NC(N(C)C)=N1 UUVWYPNAQBNQJQ-UHFFFAOYSA-N 0.000 description 1
- 238000012203 high throughput assay Methods 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 210000003026 hypopharynx Anatomy 0.000 description 1
- 229960001507 ibrutinib Drugs 0.000 description 1
- XYFPWWZEPKGCCK-GOSISDBHSA-N ibrutinib Chemical compound C1=2C(N)=NC=NC=2N([C@H]2CN(CCC2)C(=O)C=C)N=C1C(C=C1)=CC=C1OC1=CC=CC=C1 XYFPWWZEPKGCCK-GOSISDBHSA-N 0.000 description 1
- 229950007440 icotinib Drugs 0.000 description 1
- QQLKULDARVNMAL-UHFFFAOYSA-N icotinib Chemical compound C#CC1=CC=CC(NC=2C3=CC=4OCCOCCOCCOC=4C=C3N=CN=2)=C1 QQLKULDARVNMAL-UHFFFAOYSA-N 0.000 description 1
- 229960000908 idarubicin Drugs 0.000 description 1
- 229950002843 idasanutlin Drugs 0.000 description 1
- 229960003445 idelalisib Drugs 0.000 description 1
- YKLIKGKUANLGSB-HNNXBMFYSA-N idelalisib Chemical compound C1([C@@H](NC=2[C]3N=CN=C3N=CN=2)CC)=NC2=CC=CC(F)=C2C(=O)N1C1=CC=CC=C1 YKLIKGKUANLGSB-HNNXBMFYSA-N 0.000 description 1
- 229960001101 ifosfamide Drugs 0.000 description 1
- HOMGKSMUEGBAAB-UHFFFAOYSA-N ifosfamide Chemical compound ClCCNP1(=O)OCCCN1CCCl HOMGKSMUEGBAAB-UHFFFAOYSA-N 0.000 description 1
- 238000013275 image-guided biopsy Methods 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 239000012274 immune-checkpoint protein inhibitor Substances 0.000 description 1
- 238000003119 immunoblot Methods 0.000 description 1
- 238000010166 immunofluorescence Methods 0.000 description 1
- 238000002991 immunohistochemical analysis Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000007850 in situ PCR Methods 0.000 description 1
- 238000007901 in situ hybridization Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940047124 interferons Drugs 0.000 description 1
- 229940047122 interleukins Drugs 0.000 description 1
- 238000001361 intraarterial administration Methods 0.000 description 1
- 238000007917 intracranial administration Methods 0.000 description 1
- 238000007919 intrasynovial administration Methods 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 230000005865 ionizing radiation Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004768 irinotecan Drugs 0.000 description 1
- UWKQSNNFCGGAFS-XIFFEERXSA-N irinotecan Chemical compound C1=C2C(CC)=C3CN(C(C4=C([C@@](C(=O)OC4)(O)CC)C=4)=O)C=4C3=NC2=CC=C1OC(=O)N(CC1)CCC1N1CCCCC1 UWKQSNNFCGGAFS-XIFFEERXSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- 201000010982 kidney cancer Diseases 0.000 description 1
- 238000009533 lab test Methods 0.000 description 1
- 229960004891 lapatinib Drugs 0.000 description 1
- BCFGMOOMADDAQU-UHFFFAOYSA-N lapatinib Chemical compound O1C(CNCCS(=O)(=O)C)=CC=C1C1=CC=C(N=CN=C2NC=3C=C(Cl)C(OCC=4C=C(F)C=CC=4)=CC=3)C2=C1 BCFGMOOMADDAQU-UHFFFAOYSA-N 0.000 description 1
- 229950003970 larotrectinib Drugs 0.000 description 1
- 238000002430 laser surgery Methods 0.000 description 1
- 229960003784 lenvatinib Drugs 0.000 description 1
- WOSKHXYHFSIKNG-UHFFFAOYSA-N lenvatinib Chemical compound C=12C=C(C(N)=O)C(OC)=CC2=NC=CC=1OC(C=C1Cl)=CC=C1NC(=O)NC1CC1 WOSKHXYHFSIKNG-UHFFFAOYSA-N 0.000 description 1
- 229950001845 lestaurtinib Drugs 0.000 description 1
- CMJCXYNUCSMDBY-ZDUSSCGKSA-N lgx818 Chemical compound COC(=O)N[C@@H](C)CNC1=NC=CC(C=2C(=NN(C=2)C(C)C)C=2C(=C(NS(C)(=O)=O)C=C(Cl)C=2)F)=N1 CMJCXYNUCSMDBY-ZDUSSCGKSA-N 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 201000007270 liver cancer Diseases 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 229950008991 lobaplatin Drugs 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 229960002247 lomustine Drugs 0.000 description 1
- 229950004231 lucitanib Drugs 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 1
- 229960000733 mannosulfan Drugs 0.000 description 1
- UUVIQYKKKBJYJT-ZYUZMQFOSA-N mannosulfan Chemical compound CS(=O)(=O)OC[C@@H](OS(C)(=O)=O)[C@@H](O)[C@H](O)[C@H](OS(C)(=O)=O)COS(C)(=O)=O UUVIQYKKKBJYJT-ZYUZMQFOSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 229960004655 masitinib Drugs 0.000 description 1
- WJEOLQLKVOPQFV-UHFFFAOYSA-N masitinib Chemical compound C1CN(C)CCN1CC1=CC=C(C(=O)NC=2C=C(NC=3SC=C(N=3)C=3C=NC=CC=3)C(C)=CC=2)C=C1 WJEOLQLKVOPQFV-UHFFFAOYSA-N 0.000 description 1
- 238000007620 mathematical function Methods 0.000 description 1
- 229960001924 melphalan Drugs 0.000 description 1
- SGDBTWWWUNNDEQ-LBPRGKRZSA-N melphalan Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N(CCCl)CCCl)C=C1 SGDBTWWWUNNDEQ-LBPRGKRZSA-N 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000004630 mental health Effects 0.000 description 1
- 229960001428 mercaptopurine Drugs 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 229960000485 methotrexate Drugs 0.000 description 1
- 238000010208 microarray analysis Methods 0.000 description 1
- 229950010895 midostaurin Drugs 0.000 description 1
- BMGQWWVMWDBQGC-IIFHNQTCSA-N midostaurin Chemical compound CN([C@H]1[C@H]([C@]2(C)O[C@@H](N3C4=CC=CC=C4C4=C5C(=O)NCC5=C5C6=CC=CC=C6N2C5=C43)C1)OC)C(=O)C1=CC=CC=C1 BMGQWWVMWDBQGC-IIFHNQTCSA-N 0.000 description 1
- CFCUWKMKBJTWLW-BKHRDMLASA-N mithramycin Chemical compound O([C@@H]1C[C@@H](O[C@H](C)[C@H]1O)OC=1C=C2C=C3C[C@H]([C@@H](C(=O)C3=C(O)C2=C(O)C=1C)O[C@@H]1O[C@H](C)[C@@H](O)[C@H](O[C@@H]2O[C@H](C)[C@H](O)[C@H](O[C@@H]3O[C@H](C)[C@@H](O)[C@@](C)(O)C3)C2)C1)[C@H](OC)C(=O)[C@@H](O)[C@@H](C)O)[C@H]1C[C@@H](O)[C@H](O)[C@@H](C)O1 CFCUWKMKBJTWLW-BKHRDMLASA-N 0.000 description 1
- 230000000116 mitigating effect Effects 0.000 description 1
- 229960005485 mitobronitol Drugs 0.000 description 1
- 229960004857 mitomycin Drugs 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003471 mutagenic agent Substances 0.000 description 1
- 231100000707 mutagenic chemical Toxicity 0.000 description 1
- 230000003505 mutagenic effect Effects 0.000 description 1
- OLAHOMJCDNXHFI-UHFFFAOYSA-N n'-(3,5-dimethoxyphenyl)-n'-[3-(1-methylpyrazol-4-yl)quinoxalin-6-yl]-n-propan-2-ylethane-1,2-diamine Chemical compound COC1=CC(OC)=CC(N(CCNC(C)C)C=2C=C3N=C(C=NC3=CC=2)C2=CN(C)N=C2)=C1 OLAHOMJCDNXHFI-UHFFFAOYSA-N 0.000 description 1
- AXTAPYRUEKNRBA-JTQLQIEISA-N n-[(2s)-1-amino-3-(3,4-difluorophenyl)propan-2-yl]-5-chloro-4-(4-chloro-2-methylpyrazol-3-yl)furan-2-carboxamide Chemical compound CN1N=CC(Cl)=C1C1=C(Cl)OC(C(=O)N[C@H](CN)CC=2C=C(F)C(F)=CC=2)=C1 AXTAPYRUEKNRBA-JTQLQIEISA-N 0.000 description 1
- NSQSAUGJQHDYNO-UHFFFAOYSA-N n-[(4,6-dimethyl-2-oxo-1h-pyridin-3-yl)methyl]-3-[ethyl(oxan-4-yl)amino]-2-methyl-5-[4-(morpholin-4-ylmethyl)phenyl]benzamide Chemical compound C=1C(C=2C=CC(CN3CCOCC3)=CC=2)=CC(C(=O)NCC=2C(NC(C)=CC=2C)=O)=C(C)C=1N(CC)C1CCOCC1 NSQSAUGJQHDYNO-UHFFFAOYSA-N 0.000 description 1
- RJCWBNBKOKFWNY-IDPLTSGASA-N n-[(4as,6ar,6bs,8ar,12as,14ar,14bs)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,3,4,5,6,7,8,8a,14a,14b-decahydropicen-4a-yl]-2,2-difluoropropanamide Chemical compound C([C@@]12C)=C(C#N)C(=O)C(C)(C)[C@@H]1CC[C@]1(C)C2=CC(=O)[C@@H]2[C@@H]3CC(C)(C)CC[C@]3(NC(=O)C(F)(F)C)CC[C@]21C RJCWBNBKOKFWNY-IDPLTSGASA-N 0.000 description 1
- HUFOZJXAKZVRNJ-UHFFFAOYSA-N n-[3-[[2-[4-(4-acetylpiperazin-1-yl)-2-methoxyanilino]-5-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]prop-2-enamide Chemical compound COC1=CC(N2CCN(CC2)C(C)=O)=CC=C1NC(N=1)=NC=C(C(F)(F)F)C=1NC1=CC=CC(NC(=O)C=C)=C1 HUFOZJXAKZVRNJ-UHFFFAOYSA-N 0.000 description 1
- WPEWQEMJFLWMLV-UHFFFAOYSA-N n-[4-(1-cyanocyclopentyl)phenyl]-2-(pyridin-4-ylmethylamino)pyridine-3-carboxamide Chemical compound C=1C=CN=C(NCC=2C=CN=CC=2)C=1C(=O)NC(C=C1)=CC=C1C1(C#N)CCCC1 WPEWQEMJFLWMLV-UHFFFAOYSA-N 0.000 description 1
- HAYYBYPASCDWEQ-UHFFFAOYSA-N n-[5-[(3,5-difluorophenyl)methyl]-1h-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(oxan-4-ylamino)benzamide Chemical compound C1CN(C)CCN1C(C=C1NC2CCOCC2)=CC=C1C(=O)NC(C1=C2)=NNC1=CC=C2CC1=CC(F)=CC(F)=C1 HAYYBYPASCDWEQ-UHFFFAOYSA-N 0.000 description 1
- UZWDCWONPYILKI-UHFFFAOYSA-N n-[5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl]-5-fluoro-4-(7-fluoro-2-methyl-3-propan-2-ylbenzimidazol-5-yl)pyrimidin-2-amine Chemical compound C1CN(CC)CCN1CC(C=N1)=CC=C1NC1=NC=C(F)C(C=2C=C3N(C(C)C)C(C)=NC3=C(F)C=2)=N1 UZWDCWONPYILKI-UHFFFAOYSA-N 0.000 description 1
- OHDXDNUPVVYWOV-UHFFFAOYSA-N n-methyl-1-(2-naphthalen-1-ylsulfanylphenyl)methanamine Chemical compound CNCC1=CC=CC=C1SC1=CC=CC2=CC=CC=C12 OHDXDNUPVVYWOV-UHFFFAOYSA-N 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 229950004847 navitoclax Drugs 0.000 description 1
- JLYAXFNOILIKPP-KXQOOQHDSA-N navitoclax Chemical compound C([C@@H](NC1=CC=C(C=C1S(=O)(=O)C(F)(F)F)S(=O)(=O)NC(=O)C1=CC=C(C=C1)N1CCN(CC1)CC1=C(CCC(C1)(C)C)C=1C=CC(Cl)=CC=1)CSC=1C=CC=CC=1)CN1CCOCC1 JLYAXFNOILIKPP-KXQOOQHDSA-N 0.000 description 1
- 229950007221 nedaplatin Drugs 0.000 description 1
- 229950008835 neratinib Drugs 0.000 description 1
- ZNHPZUKZSNBOSQ-BQYQJAHWSA-N neratinib Chemical compound C=12C=C(NC\C=C\CN(C)C)C(OCC)=CC2=NC=C(C#N)C=1NC(C=C1Cl)=CC=C1OCC1=CC=CC=N1 ZNHPZUKZSNBOSQ-BQYQJAHWSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229960001346 nilotinib Drugs 0.000 description 1
- HHZIURLSWUIHRB-UHFFFAOYSA-N nilotinib Chemical compound C1=NC(C)=CN1C1=CC(NC(=O)C=2C=C(NC=3N=C(C=CN=3)C=3C=NC=CC=3)C(C)=CC=2)=CC(C(F)(F)F)=C1 HHZIURLSWUIHRB-UHFFFAOYSA-N 0.000 description 1
- 229960001420 nimustine Drugs 0.000 description 1
- VFEDRRNHLBGPNN-UHFFFAOYSA-N nimustine Chemical compound CC1=NC=C(CNC(=O)N(CCCl)N=O)C(N)=N1 VFEDRRNHLBGPNN-UHFFFAOYSA-N 0.000 description 1
- 229960004378 nintedanib Drugs 0.000 description 1
- XZXHXSATPCNXJR-ZIADKAODSA-N nintedanib Chemical compound O=C1NC2=CC(C(=O)OC)=CC=C2\C1=C(C=1C=CC=CC=1)\NC(C=C1)=CC=C1N(C)C(=O)CN1CCN(C)CC1 XZXHXSATPCNXJR-ZIADKAODSA-N 0.000 description 1
- 229950011068 niraparib Drugs 0.000 description 1
- PCHKPVIQAHNQLW-CQSZACIVSA-N niraparib Chemical compound N1=C2C(C(=O)N)=CC=CC2=CN1C(C=C1)=CC=C1[C@@H]1CCCNC1 PCHKPVIQAHNQLW-CQSZACIVSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 238000013546 non-drug therapy Methods 0.000 description 1
- 231100000862 numbness Toxicity 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 229960000572 olaparib Drugs 0.000 description 1
- FAQDUNYVKQKNLD-UHFFFAOYSA-N olaparib Chemical compound FC1=CC=C(CC2=C3[CH]C=CC=C3C(=O)N=N2)C=C1C(=O)N(CC1)CCN1C(=O)C1CC1 FAQDUNYVKQKNLD-UHFFFAOYSA-N 0.000 description 1
- 229950008128 omaveloxolone Drugs 0.000 description 1
- 229950000307 onalespib Drugs 0.000 description 1
- IFRGXKKQHBVPCQ-UHFFFAOYSA-N onalespib Chemical compound C1=C(O)C(C(C)C)=CC(C(=O)N2CC3=CC(CN4CCN(C)CC4)=CC=C3C2)=C1O IFRGXKKQHBVPCQ-UHFFFAOYSA-N 0.000 description 1
- 244000309459 oncolytic virus Species 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000003300 oropharynx Anatomy 0.000 description 1
- 229960003278 osimertinib Drugs 0.000 description 1
- DUYJMQONPNNFPI-UHFFFAOYSA-N osimertinib Chemical compound COC1=CC(N(C)CCN(C)C)=C(NC(=O)C=C)C=C1NC1=NC=CC(C=2C3=CC=CC=C3N(C)C=2)=N1 DUYJMQONPNNFPI-UHFFFAOYSA-N 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 229960001756 oxaliplatin Drugs 0.000 description 1
- DWAFYCQODLXJNR-BNTLRKBRSA-L oxaliplatin Chemical compound O1C(=O)C(=O)O[Pt]11N[C@@H]2CCCC[C@H]2N1 DWAFYCQODLXJNR-BNTLRKBRSA-L 0.000 description 1
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 description 1
- 229960004390 palbociclib Drugs 0.000 description 1
- AHJRHEGDXFFMBM-UHFFFAOYSA-N palbociclib Chemical compound N1=C2N(C3CCCC3)C(=O)C(C(=O)C)=C(C)C2=CN=C1NC(N=C1)=CC=C1N1CCNCC1 AHJRHEGDXFFMBM-UHFFFAOYSA-N 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940121656 pd-l1 inhibitor Drugs 0.000 description 1
- 210000003899 penis Anatomy 0.000 description 1
- FPVKHBSQESCIEP-JQCXWYLXSA-N pentostatin Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(N=CNC[C@H]2O)=C2N=C1 FPVKHBSQESCIEP-JQCXWYLXSA-N 0.000 description 1
- 229960002340 pentostatin Drugs 0.000 description 1
- 210000004912 pericardial fluid Anatomy 0.000 description 1
- 210000003668 pericyte Anatomy 0.000 description 1
- 238000012831 peritoneal equilibrium test Methods 0.000 description 1
- 229950001457 pexidartinib Drugs 0.000 description 1
- JGWRKYUXBBNENE-UHFFFAOYSA-N pexidartinib Chemical compound C1=NC(C(F)(F)F)=CC=C1CNC(N=C1)=CC=C1CC1=CNC2=NC=C(Cl)C=C12 JGWRKYUXBBNENE-UHFFFAOYSA-N 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- IIMIOEBMYPRQGU-UHFFFAOYSA-L picoplatin Chemical compound N.[Cl-].[Cl-].[Pt+2].CC1=CC=CC=N1 IIMIOEBMYPRQGU-UHFFFAOYSA-L 0.000 description 1
- 229950005566 picoplatin Drugs 0.000 description 1
- 229950004941 pictilisib Drugs 0.000 description 1
- LHNIIDJUOCFXAP-UHFFFAOYSA-N pictrelisib Chemical compound C1CN(S(=O)(=O)C)CCN1CC1=CC2=NC(C=3C=4C=NNC=4C=CC=3)=NC(N3CCOCC3)=C2S1 LHNIIDJUOCFXAP-UHFFFAOYSA-N 0.000 description 1
- 229950006101 pinometostat Drugs 0.000 description 1
- 229960001221 pirarubicin Drugs 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 229960002169 plerixafor Drugs 0.000 description 1
- YIQPUIGJQJDJOS-UHFFFAOYSA-N plerixafor Chemical compound C=1C=C(CN2CCNCCCNCCNCCC2)C=CC=1CN1CCCNCCNCCCNCC1 YIQPUIGJQJDJOS-UHFFFAOYSA-N 0.000 description 1
- 210000004910 pleural fluid Anatomy 0.000 description 1
- 229960003171 plicamycin Drugs 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229960001131 ponatinib Drugs 0.000 description 1
- PHXJVRSECIGDHY-UHFFFAOYSA-N ponatinib Chemical compound C1CN(C)CCN1CC(C(=C1)C(F)(F)F)=CC=C1NC(=O)C1=CC=C(C)C(C#CC=2N3N=CC=CC3=NC=2)=C1 PHXJVRSECIGDHY-UHFFFAOYSA-N 0.000 description 1
- 238000012636 positron electron tomography Methods 0.000 description 1
- 238000012877 positron emission topography Methods 0.000 description 1
- 229950009876 poziotinib Drugs 0.000 description 1
- 238000004632 predicting treatment efficacy Methods 0.000 description 1
- 229960004694 prednimustine Drugs 0.000 description 1
- CPTBDICYNRMXFX-UHFFFAOYSA-N procarbazine Chemical compound CNNCC1=CC=C(C(=O)NC(C)C)C=C1 CPTBDICYNRMXFX-UHFFFAOYSA-N 0.000 description 1
- 229960000624 procarbazine Drugs 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 238000000575 proteomic method Methods 0.000 description 1
- 238000002661 proton therapy Methods 0.000 description 1
- 238000007388 punch biopsy Methods 0.000 description 1
- 239000000649 purine antagonist Substances 0.000 description 1
- 239000003790 pyrimidine antagonist Substances 0.000 description 1
- 238000012175 pyrosequencing Methods 0.000 description 1
- 229940075576 pyrotinib Drugs 0.000 description 1
- 229950001626 quizartinib Drugs 0.000 description 1
- CVWXJKQAOSCOAB-UHFFFAOYSA-N quizartinib Chemical compound O1C(C(C)(C)C)=CC(NC(=O)NC=2C=CC(=CC=2)C=2N=C3N(C4=CC=C(OCCN5CCOCC5)C=C4S3)C=2)=N1 CVWXJKQAOSCOAB-UHFFFAOYSA-N 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 229960004432 raltitrexed Drugs 0.000 description 1
- 229960002185 ranimustine Drugs 0.000 description 1
- ZAHRKKWIAAJSAO-UHFFFAOYSA-N rapamycin Natural products COCC(O)C(=C/C(C)C(=O)CC(OC(=O)C1CCCCN1C(=O)C(=O)C2(O)OC(CC(OC)C(=CC=CC=CC(C)CC(C)C(=O)C)C)CCC2C)C(C)CC3CCC(O)C(C3)OC)C ZAHRKKWIAAJSAO-UHFFFAOYSA-N 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 229960004836 regorafenib Drugs 0.000 description 1
- FNHKPVJBJVTLMP-UHFFFAOYSA-N regorafenib Chemical compound C1=NC(C(=O)NC)=CC(OC=2C=C(F)C(NC(=O)NC=3C=C(C(Cl)=CC=3)C(F)(F)F)=CC=2)=C1 FNHKPVJBJVTLMP-UHFFFAOYSA-N 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229950003687 ribociclib Drugs 0.000 description 1
- 229960001302 ridaforolimus Drugs 0.000 description 1
- 229950009855 rociletinib Drugs 0.000 description 1
- MNDBXUUTURYVHR-UHFFFAOYSA-N roflumilast Chemical compound FC(F)OC1=CC=C(C(=O)NC=2C(=CN=CC=2Cl)Cl)C=C1OCC1CC1 MNDBXUUTURYVHR-UHFFFAOYSA-N 0.000 description 1
- 229960002586 roflumilast Drugs 0.000 description 1
- VHXNKPBCCMUMSW-FQEVSTJZSA-N rubitecan Chemical compound C1=CC([N+]([O-])=O)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 VHXNKPBCCMUMSW-FQEVSTJZSA-N 0.000 description 1
- 229950009213 rubitecan Drugs 0.000 description 1
- 229950004707 rucaparib Drugs 0.000 description 1
- HMABYWSNWIZPAG-UHFFFAOYSA-N rucaparib Chemical compound C1=CC(CNC)=CC=C1C(N1)=C2CCNC(=O)C3=C2C1=CC(F)=C3 HMABYWSNWIZPAG-UHFFFAOYSA-N 0.000 description 1
- 229960000215 ruxolitinib Drugs 0.000 description 1
- HFNKQEVNSGCOJV-OAHLLOKOSA-N ruxolitinib Chemical compound C1([C@@H](CC#N)N2N=CC(=C2)C=2C=3C=CNC=3N=CN=2)CCCC1 HFNKQEVNSGCOJV-OAHLLOKOSA-N 0.000 description 1
- 210000003079 salivary gland Anatomy 0.000 description 1
- 238000003118 sandwich ELISA Methods 0.000 description 1
- 238000007480 sanger sequencing Methods 0.000 description 1
- DFJSJLGUIXFDJP-UHFFFAOYSA-N sapitinib Chemical compound C1CN(CC(=O)NC)CCC1OC(C(=CC1=NC=N2)OC)=CC1=C2NC1=CC=CC(Cl)=C1F DFJSJLGUIXFDJP-UHFFFAOYSA-N 0.000 description 1
- 229950006474 sapitinib Drugs 0.000 description 1
- 229950009919 saracatinib Drugs 0.000 description 1
- OUKYUETWWIPKQR-UHFFFAOYSA-N saracatinib Chemical compound C1CN(C)CCN1CCOC1=CC(OC2CCOCC2)=C(C(NC=2C(=CC=C3OCOC3=2)Cl)=NC=N2)C2=C1 OUKYUETWWIPKQR-UHFFFAOYSA-N 0.000 description 1
- 229960005399 satraplatin Drugs 0.000 description 1
- 210000004706 scrotum Anatomy 0.000 description 1
- 229950010613 selinexor Drugs 0.000 description 1
- 229950010746 selumetinib Drugs 0.000 description 1
- CYOHGALHFOKKQC-UHFFFAOYSA-N selumetinib Chemical compound OCCONC(=O)C=1C=C2N(C)C=NC2=C(F)C=1NC1=CC=C(Br)C=C1Cl CYOHGALHFOKKQC-UHFFFAOYSA-N 0.000 description 1
- 210000001625 seminal vesicle Anatomy 0.000 description 1
- 229960003440 semustine Drugs 0.000 description 1
- 238000007841 sequencing by ligation Methods 0.000 description 1
- QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C[C@@H](O)[C@H](OC)C[C@@H]1C[C@@H](C)[C@H]1OC(=O)[C@@H]2CCCCN2C(=O)C(=O)[C@](O)(O2)[C@H](C)CC[C@H]2C[C@H](OC)/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 description 1
- 229960002930 sirolimus Drugs 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 1
- 201000000849 skin cancer Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 229960005325 sonidegib Drugs 0.000 description 1
- VZZJRYRQSPEMTK-CALCHBBNSA-N sonidegib Chemical compound C1[C@@H](C)O[C@@H](C)CN1C(N=C1)=CC=C1NC(=O)C1=CC=CC(C=2C=CC(OC(F)(F)F)=CC=2)=C1C VZZJRYRQSPEMTK-CALCHBBNSA-N 0.000 description 1
- 229960003787 sorafenib Drugs 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960001052 streptozocin Drugs 0.000 description 1
- ZSJLQEPLLKMAKR-GKHCUFPYSA-N streptozocin Chemical compound O=NN(C)C(=O)N[C@H]1[C@@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O ZSJLQEPLLKMAKR-GKHCUFPYSA-N 0.000 description 1
- 210000002536 stromal cell Anatomy 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 210000001179 synovial fluid Anatomy 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 229960001967 tacrolimus Drugs 0.000 description 1
- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
- 229950001269 taselisib Drugs 0.000 description 1
- 229950004774 tazemetostat Drugs 0.000 description 1
- 210000001138 tear Anatomy 0.000 description 1
- 229940066453 tecentriq Drugs 0.000 description 1
- 229960001674 tegafur Drugs 0.000 description 1
- WFWLQNSHRPWKFK-ZCFIWIBFSA-N tegafur Chemical compound O=C1NC(=O)C(F)=CN1[C@@H]1OCCC1 WFWLQNSHRPWKFK-ZCFIWIBFSA-N 0.000 description 1
- 229960004964 temozolomide Drugs 0.000 description 1
- 229960000235 temsirolimus Drugs 0.000 description 1
- QFJCIRLUMZQUOT-UHFFFAOYSA-N temsirolimus Natural products C1CC(O)C(OC)CC1CC(C)C1OC(=O)C2CCCCN2C(=O)C(=O)C(O)(O2)C(C)CCC2CC(OC)C(C)=CC=CC=CC(C)CC(C)C(=O)C(OC)C(O)C(C)=CC(C)C(=O)C1 QFJCIRLUMZQUOT-UHFFFAOYSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 210000001541 thymus gland Anatomy 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 229950009158 tipifarnib Drugs 0.000 description 1
- PLHJCIYEEKOWNM-HHHXNRCGSA-N tipifarnib Chemical compound CN1C=NC=C1[C@](N)(C=1C=C2C(C=3C=C(Cl)C=CC=3)=CC(=O)N(C)C2=CC=1)C1=CC=C(Cl)C=C1 PLHJCIYEEKOWNM-HHHXNRCGSA-N 0.000 description 1
- 229950005976 tivantinib Drugs 0.000 description 1
- 229960001350 tofacitinib Drugs 0.000 description 1
- UJLAWZDWDVHWOW-YPMHNXCESA-N tofacitinib Chemical compound C[C@@H]1CCN(C(=O)CC#N)C[C@@H]1N(C)C1=NC=NC2=C1C=CN2 UJLAWZDWDVHWOW-YPMHNXCESA-N 0.000 description 1
- 210000002105 tongue Anatomy 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- MFAQYJIYDMLAIM-UHFFFAOYSA-N torkinib Chemical compound C12=C(N)N=CN=C2N(C(C)C)N=C1C1=CC2=CC(O)=CC=C2N1 MFAQYJIYDMLAIM-UHFFFAOYSA-N 0.000 description 1
- 229960000575 trastuzumab Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- 229960003181 treosulfan Drugs 0.000 description 1
- 150000004654 triazenes Chemical class 0.000 description 1
- 229960004560 triaziquone Drugs 0.000 description 1
- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 229960000875 trofosfamide Drugs 0.000 description 1
- UMKFEPPTGMDVMI-UHFFFAOYSA-N trofosfamide Chemical compound ClCCN(CCCl)P1(=O)OCCCN1CCCl UMKFEPPTGMDVMI-UHFFFAOYSA-N 0.000 description 1
- 229940121344 umbralisib Drugs 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
- 229950005787 uprosertib Drugs 0.000 description 1
- 229960001055 uracil mustard Drugs 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 229960000653 valrubicin Drugs 0.000 description 1
- ZOCKGBMQLCSHFP-KQRAQHLDSA-N valrubicin Chemical compound O([C@H]1C[C@](CC2=C(O)C=3C(=O)C4=CC=CC(OC)=C4C(=O)C=3C(O)=C21)(O)C(=O)COC(=O)CCCC)[C@H]1C[C@H](NC(=O)C(F)(F)F)[C@H](O)[C@H](C)O1 ZOCKGBMQLCSHFP-KQRAQHLDSA-N 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- UHTHHESEBZOYNR-UHFFFAOYSA-N vandetanib Chemical compound COC1=CC(C(/N=CN2)=N/C=3C(=CC(Br)=CC=3)F)=C2C=C1OCC1CCN(C)CC1 UHTHHESEBZOYNR-UHFFFAOYSA-N 0.000 description 1
- 229950006605 varlitinib Drugs 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229950011257 veliparib Drugs 0.000 description 1
- JNAHVYVRKWKWKQ-CYBMUJFWSA-N veliparib Chemical compound N=1C2=CC=CC(C(N)=O)=C2NC=1[C@@]1(C)CCCN1 JNAHVYVRKWKWKQ-CYBMUJFWSA-N 0.000 description 1
- 229960001722 verapamil Drugs 0.000 description 1
- 201000010653 vesiculitis Diseases 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 229960004449 vismodegib Drugs 0.000 description 1
- BPQMGSKTAYIVFO-UHFFFAOYSA-N vismodegib Chemical compound ClC1=CC(S(=O)(=O)C)=CC=C1C(=O)NC1=CC=C(Cl)C(C=2N=CC=CC=2)=C1 BPQMGSKTAYIVFO-UHFFFAOYSA-N 0.000 description 1
- 229950007259 vistusertib Drugs 0.000 description 1
- 229950003081 volasertib Drugs 0.000 description 1
- SXNJFOWDRLKDSF-STROYTFGSA-N volasertib Chemical compound C1CN([C@H]2CC[C@@H](CC2)NC(=O)C2=CC=C(C(=C2)OC)NC=2N=C3N(C(C)C)[C@@H](C(N(C)C3=CN=2)=O)CC)CCN1CC1CC1 SXNJFOWDRLKDSF-STROYTFGSA-N 0.000 description 1
- 210000003905 vulva Anatomy 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 230000036642 wellbeing Effects 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
- 229960000641 zorubicin Drugs 0.000 description 1
- FBTUMDXHSRTGRV-ALTNURHMSA-N zorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(\C)=N\NC(=O)C=1C=CC=CC=1)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 FBTUMDXHSRTGRV-ALTNURHMSA-N 0.000 description 1
Images
Classifications
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B45/00—ICT specially adapted for bioinformatics-related data visualisation, e.g. displaying of maps or networks
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
- C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
- C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F16/00—Information retrieval; Database structures therefor; File system structures therefor
- G06F16/20—Information retrieval; Database structures therefor; File system structures therefor of structured data, e.g. relational data
- G06F16/28—Databases characterised by their database models, e.g. relational or object models
- G06F16/284—Relational databases
- G06F16/285—Clustering or classification
-
- G—PHYSICS
- G06—COMPUTING; CALCULATING OR COUNTING
- G06F—ELECTRIC DIGITAL DATA PROCESSING
- G06F17/00—Digital computing or data processing equipment or methods, specially adapted for specific functions
- G06F17/10—Complex mathematical operations
- G06F17/18—Complex mathematical operations for evaluating statistical data, e.g. average values, frequency distributions, probability functions, regression analysis
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B25/00—ICT specially adapted for hybridisation; ICT specially adapted for gene or protein expression
- G16B25/10—Gene or protein expression profiling; Expression-ratio estimation or normalisation
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B30/00—ICT specially adapted for sequence analysis involving nucleotides or amino acids
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- G16B40/20—Supervised data analysis
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B40/00—ICT specially adapted for biostatistics; ICT specially adapted for bioinformatics-related machine learning or data mining, e.g. knowledge discovery or pattern finding
- G16B40/30—Unsupervised data analysis
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B5/00—ICT specially adapted for modelling or simulations in systems biology, e.g. gene-regulatory networks, protein interaction networks or metabolic networks
- G16B5/20—Probabilistic models
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16B—BIOINFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR GENETIC OR PROTEIN-RELATED DATA PROCESSING IN COMPUTATIONAL MOLECULAR BIOLOGY
- G16B50/00—ICT programming tools or database systems specially adapted for bioinformatics
- G16B50/30—Data warehousing; Computing architectures
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H10/00—ICT specially adapted for the handling or processing of patient-related medical or healthcare data
- G16H10/20—ICT specially adapted for the handling or processing of patient-related medical or healthcare data for electronic clinical trials or questionnaires
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
- G16H20/10—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to drugs or medications, e.g. for ensuring correct administration to patients
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H20/00—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance
- G16H20/40—ICT specially adapted for therapies or health-improving plans, e.g. for handling prescriptions, for steering therapy or for monitoring patient compliance relating to mechanical, radiation or invasive therapies, e.g. surgery, laser therapy, dialysis or acupuncture
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/30—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for calculating health indices; for individual health risk assessment
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/50—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for simulation or modelling of medical disorders
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
- G16H50/70—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for mining of medical data, e.g. analysing previous cases of other patients
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
- G16H70/00—ICT specially adapted for the handling or processing of medical references
- G16H70/20—ICT specially adapted for the handling or processing of medical references relating to practices or guidelines
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/156—Polymorphic or mutational markers
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q2600/00—Oligonucleotides characterized by their use
- C12Q2600/158—Expression markers
Definitions
- aspects of the technology described herein relate to predicting treatment efficacy based on subject (e.g., patient) specific information such as a subject's (e.g., patient's) biomarkers.
- Some aspects of the technology described herein relate to determining therapy scores (for one or more potential treatments) and determining therapy scores before and after a treatment. Some aspects of the technology described herein relate to generating a graphical user interface (GUI) for visualizing therapy scores.
- GUI graphical user interface
- Some aspects of the technology described herein relate to determining impact scores (for treatments). Some aspects of the technology described herein relate to generating a graphical user interface for visualizing impact scores.
- Some aspects of the technology described herein relate to determining normalized biomarker scores for a subject. Some aspects of the technology described herein relate to identifying the subject as a member of one or more cohorts using normalized biomarkers scores. Some aspects of the technology described herein relate to outputting such information (e.g., to one or more users). Some aspects of the technology described herein relate to potential inclusion or exclusion of a subject from a clinical trial.
- Correctly selecting one or more effective therapies for a subject (e.g., a patient) with cancer or determining the effectiveness of a treatment can be crucial for the survival and overall wellbeing of that subject. Advances in identifying effective therapies and understanding their effectiveness or otherwise aiding in personalized care of patients with cancer are needed.
- GUI graphical user interface
- Systems and methods for determining therapy scores for multiple therapies based on normalized biomarker scores comprises, in some embodiments, accessing sequence data for a subject, accessing biomarker information indicating distribution of values for biomarkers associated with multiple therapies, determining normalized biomarker scores for the subject using sequencing data and biomarker information, and determining therapy scores for the multiple therapies based on normalized biomarker scores.
- GUI graphical user interface
- Systems and methods for determining impact score for a candidate therapy using first and second normalized biomarker scores comprises, in some embodiments, obtaining first sequencing data for a subject prior to administration of candidate therapy, obtaining second sequencing data for a subject subsequent to administration of candidate therapy, accessing biomarker information indicating distribution of values for a biomarker associated with the candidate therapy, determining first and second biomarker scores for the subject using first sequencing data, second sequencing data, and biomarker information, and determining impact score for the candidate therapy using first and second normalized biomarker scores.
- GUI graphical user interface
- Systems and methods for determining therapy scores for at least two selected therapies based on normalized biomarker scores for the at least three biomarkers comprises, in some embodiments, obtaining sequencing data for a subject, accessing biomarker information for at least three biomarkers associated with at least two selected therapies, determining first and second sets of normalized biomarker scores for the subject using sequencing data and biomarker information, and determining therapy scores for the at least two selected therapies based on normalized biomarker scores for the at least three biomarkers.
- GUI graphical user interface
- Systems and methods for obtaining first and second therapy scores for first and second therapies comprises, in some embodiments, obtaining sequence data for a subject, accessing biomarker information indicating distribution of values for biomarkers associated with multiple therapies, determining first and second sets of normalized biomarker scores for the subject using sequencing data and biomarker information, and obtaining first and second therapy scores for first and second therapies.
- GUI graphical user interface
- Systems and methods for identifying a subject as a member of a cohort using normalized biomarker scores comprises, in some embodiments, obtaining sequencing data for a subject, accessing biomarker information indicating distribution of values for biomarkers associated with multiple therapies, determining normalized biomarker scores for the subject using sequencing data and biomarker information, and identifying the subject as a member of a cohort using normalized biomarker scores.
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomark
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies
- a method comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies, each of the therapy scores indicative of predicted response of the subject to administration of a respective therapy in the plurality of therapies.
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- a method comprising: using at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information; a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a
- a method comprising using the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized scores as input to the statistical model to obtain a second therapy
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input
- a method comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized biomarker scores
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one
- a method comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one or more cohorts in which the subject is a member.
- FIG. 1 A is a diagram of an illustrative process for obtaining patient data and providing that data to a doctor, in accordance with some embodiments of the technology described herein.
- FIG. 1 B is a block diagram of patient data that may be presented to a user, in accordance with some embodiments of the technology described herein.
- FIG. 1 C is a graphical representation of patient data that may be presented to a user, in accordance with some embodiments of the technology described herein.
- FIG. 2 A is a flow chart of an illustrative process for determining therapy scores for multiple therapies based normalized biomarker scores, in accordance with some embodiments of the technology described herein.
- FIG. 2 B is a flow chart of an illustrative process for determining impact score for a candidate therapy using a first normalized biomarker score and a second normalized biomarker score, in accordance with some embodiments of the technology described herein.
- FIG. 2 C is a flow chart of an illustrative process for determining therapy scores for that at least two selected therapies based on normalized biomarker scores for the at least three biomarkers, in accordance with some embodiments of the technology described herein.
- FIG. 2 D is a flow chart of an illustrative process for obtaining first and second therapy scores for first and second therapies, in accordance with some embodiments of the technology described herein.
- FIG. 2 E is a flow chart of an illustrative process for identifying a subject as a member of a cohort using normalized biomarker scores, in accordance with some embodiments of the technology described herein.
- FIG. 3 is a graphical representation of biomarker value distribution for a large patient cohort, as determined in accordance with some embodiments of the technology described herein.
- FIG. 4 is a graphical representation of patient therapy scores calculated as the sum of positive and negative biomarkers, in accordance with some embodiments of the technology described herein.
- FIG. 5 is a graphical representation of patient therapy scores calculated for multiple therapies for a patient that has been determined as responsive (Patient 1) or non-responsive (Patient 2) to an anti-PD1 therapy (Pembrolizumab), in accordance with some embodiments of the technology described herein.
- FIG. 6 A is a screenshot presenting normalized biomarker values calculated for different immunotherapies, in accordance with some embodiments of the technology described herein.
- FIG. 6 B is a screenshot presenting patient therapy scores for different immunotherapies calculated using normalized biomarker values, in accordance with some embodiments of the technology described herein.
- FIG. 6 C is a screenshot presenting information related to biomarkers used to calculate patient therapy scores, in accordance with some embodiments of the technology described herein.
- FIG. 7 A is a graphical representation of therapy scores calculated for patients treated with an anti-PD1 therapy (Pembrolizumab), in accordance with some embodiments of the technology described herein.
- Patients with progressive disease (PD) are shown in red
- patients with stable disease (SD) are shown in light blue
- patients with complete response (CR) are shown in blue.
- FIG. 7 B is a graphical representation of therapy scores calculated for patients treated with an anti-CTLA4 therapy (Ipilimumab), in accordance with some embodiments of the technology described herein.
- Patients with progressive disease (PD) are shown as a dark solid line
- patients with stable disease (SD) are shown as a light grey striped line
- patients with partial response (PR) are shown in a dark grey striped line.
- FIG. 7 C is a graphical representation of therapy scores calculated for patients treated with an anti-PD1 therapy (Pembrolizumab), in accordance with some embodiments of the technology described herein.
- Patients with progressive disease (PD) are shown as a dark solid line
- patients with stable disease (SD) are shown as a light grey striped line
- patients with partial response (PR) are shown in a dark grey striped line.
- FIG. 8 A is a graphical representation of therapy scores calculated without additional weight optimization in a machine learning-based optimization of biomarker importance, in accordance with some embodiments of the technology described herein.
- Patients with progressive disease (PD) are shown as a dark solid line
- patients with stable disease (SD) are shown as a light grey striped line
- patients with partial response (PR) are shown in a dark grey striped line.
- FIG. 8 B is a graphical representation of therapy scores calculated with machine-adapted weights, in accordance with some embodiments of the technology described herein.
- Patients with progressive disease (PD) are shown as a dark solid line
- patients with stable disease (SD) are shown as a light grey striped line
- patients with partial response (PR) are shown in a dark grey striped line.
- FIG. 8 C is a graphical representation of biomarker importance in terms of feature importance calculated with forest regression algorithms, in accordance with some embodiments of the technology described herein.
- FIG. 8 D is a graphical representation of biomarker weights recalculated with a logistic regression model to improve prediction of therapy response, in accordance with some embodiments of the technology described herein.
- FIG. 9 is a graphic illustrating different types of screens that may be shown to a user of the software program.
- FIG. 10 is a screenshot presenting the selected patient's report including information related to the patient's sequencing data, the patient, and the patient's cancer.
- FIG. 11 is a screenshot presenting information related to anti-PD1 immunotherapy provided in response to selecting anti-PD1 immunotherapy (as shown by highlighting) in the immunotherapy biomarkers portion of the screen (as shown in the left panel).
- FIG. 12 is a screenshot presenting selection of mutational burden biomarker by a user.
- FIG. 13 is a screenshot presenting information relating to the mutational burden biomarker (as shown in the middle panel) provided in response to the user selecting the mutational burden biomarker.
- FIG. 14 is a screenshot presenting clinical trial data relating to anti-PD1 therapy effectivity in patients having stage IV metastatic melanoma (as shown in the right panel) provided in response to the user selecting anti-PD1 immunotherapy (as shown in the left panel).
- FIG. 15 is a block diagram of an illustrative computer system that may be used in implementing some embodiments of the technology described herein.
- a second biomarker may be predictive of the efficacy of the candidate therapy for a second or further cohorts (or groups) of subjects (e.g., patients), but fail to do so for the first cohort (or group).
- different individual biomarkers may suggest different courses of action.
- using a single biomarker to determine the efficacy of a candidate treatment is problematic for many patients. Even if a single biomarker having the highest correlation with response for a candidate treatment were chosen, it may still have a weak predictive capability without taking into account the full scope of each patient's case and personal condition.
- biomarker's values Another problem with conventional single-parameter methodology is the heterogeneity of a biomarker's values. Due to the variation in measurements of different clinics and clinical trials, potential biomarkers become incomparable between subjects (e.g., patients) from different hospitals or clinical settings. The biomarker values defined in one study could significantly differ from the results of the same measurements performed at a different site or on different equipment. While the relative meaning of a biomarker may remain unchanged—for example, a “high” biomarker value is bad or “low” value is good for predicting therapy efficacy—experimental cut-off or threshold values for “high” or “low” definitions often significantly vary among studies.
- the inventors have developed techniques for predicting the efficacy of therapies for a subject that address (e.g., mitigate or avoid) the above-described problems of conventional single-biomarker approaches.
- the inventors have developed techniques of predicting therapy efficacy using multiple biomarkers (e.g., biomarkers associated with positive therapeutic response or non-positive therapeutic response to a particular therapy or type of therapy).
- biomarkers e.g., biomarkers associated with positive therapeutic response or non-positive therapeutic response to a particular therapy or type of therapy.
- different biomarkers may have values in vastly different ranges.
- the inventors In order to use multiple such biomarkers in a single common quantitative framework for predicting therapy efficacy, the inventors have developed a technique for normalizing the values of the biomarkers relative to their variation in reference populations, thereby placing them on a common scale.
- the inventors have also recognized that comparing biomarker scores of a patient to those of other patients may be used to compute normalized biomarker scores. Further, such normalized biomarker scores may be utilized to more accurately predict a patient's response to a therapy. The inventors have specifically developed techniques for simultaneous analysis of the normalized biomarkers as described herein.
- cancer cells e.g., tumor cells
- cancer microenvironments from one or more biological samples obtained from individual patients.
- This information can be used to determine a large number of parameters (or biomarkers) for each patient and, potentially, use this information to identify effective therapies and/or select one or more effective therapies for the subject (e.g., the patient).
- This information may also be used to determine how a subject (e.g., a patient) is responding over time to a treatment and, if necessary, to select a new therapy or therapies for the subject (e.g., the patient) as necessary.
- This information may also be used to determine whether the subject (e.g., the patient) should be included or excluded from participating in a clinical trial.
- aspects of the technology described herein relate to systems and methods and for predicting a patient's response to a therapy based on patient specific information such as a patient's biomarker values.
- predicting a patient's response to a therapy comprises determining normalized biomarker scores (also described as “normalized scores”) using sequencing data and biomarker information.
- predicting a patient's response to a therapy comprises determining therapy scores for the multiple therapies based on normalized biomarker scores.
- a therapy score for a therapy is a numerical value that may provide a quantitative measure of the therapy's predicted efficacy in treating a subject.
- determining a patient's response to a therapy comprises determining an impact score based on normalized biomarker scores.
- An impact score for a therapy is a numerical value that may provide a quantitative measure of the therapy's current efficacy (impact) in treating a subject.
- Such methods and systems may be useful for clinical purposes including, for example, selecting a treatment, evaluating suitability of a patient for participating in a clinical trial, or determining a course of treatment for a subject (e.g., a patient).
- the methods and systems described herein may also be useful for non-clinical applications including (as a non-limiting example) research purposes such as, e.g., studying the biological pathways and/or biological processes targeted by a therapy, and developing new therapies for cancer based on such studies.
- systems which present this information in a comprehensive and useable format will be needed to facilitate treatment of patients with such conditions. Therefore, provided herein are systems and methods for analyzing patient specific information that result in a prediction of a patient's response or lack thereof to a treatment.
- Such an analysis takes into consideration a global view of patient information to make a prediction regarding the patient's response to a therapy that is well-informed and comprehensive.
- the analysis described herein is a global analysis of patient specific information. Certain aspects of the described methods take into account biological data generated from analysis of at least one biological sample of a subject. Other aspects of the described methods take into account patient specific information related to the overall health and/or lifestyle of a patient (e.g., personal habits, environmental factors) that may play a role in whether a patient responds to a therapy.
- techniques described herein provide for improvements over conventional computer-implemented techniques for analysis of medical data such as evaluation of expression data (e.g., RNA expression data) and determining whether one or more therapies (e.g., targeted therapies, radiotherapies, and/or immunotherapies) will be effective in treating the subject.
- improvements include, but are not limited to, improvements in predictive power regarding the effectiveness of candidate treatments for a subject over conventional single biomarker treatments.
- some embodiments of the technology provided herein are directed to graphical user interfaces that present oncological data in a new way which is compact and highly informative.
- These graphical user interfaces not only reduce the cognitive load on a user (e.g., a doctor or other medical professional) working with them, but may serve to reduce clinician errors and improve the functionality of a computer by providing all needed information in a single interactive interface. This could eliminate the need for a user (e.g., a clinician) to consult different sources of information (e.g., view multiple different webpages, use multiple different application programs, etc.), which would otherwise place an additional burden on the processing, memory, and communications resources of the computer(s) used by such a user (e.g., a clinician).
- a user e.g., a clinician
- sequence data such as that from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy, or from other tissues of the patient are suitable although any type of sequence data may be used.
- Additional data concerning other patient, cancerous cell, or tumor parameters, or microenvironment parameters may also be considered including, but not limited to: tumor and/or cancerous cell proteomic analysis; immunohistochemistry staining; flow cytometry; standard clinical measurements of blood, urine and other biological fluids; biopsies of one or more tumors and organs; images obtained by any methods, including X-ray, ultrasonic, sonic, or magnetic resonance imaging scintillation studies, etc.
- all features that distinguish one patient from another including, but not limited to, disease stage, sex, age, tumor mutations, cancerous cell mutations, blood analysis, IHC of biopsy, etc. are called patient parameters and may be included in the algorithm.
- the parameters of the subject e.g., the patient
- the type of tumor, or the type of cancerous cell may have been identified in group clinical trials that were published in scientific journals or actively used in clinically approved analyses, guidelines of treatment options (FDA, NIH, NCCN, CPIC, etc.) or elsewhere.
- These parameters are biomarkers, the presence or absence of which and/or levels of which may be statistically significantly correlated (e.g., the correlation may be at least a threshold amount away from zero) with treatment response or patient survival.
- Certain techniques described herein are designed to use any reliable and available information about discovered biomarkers to simultaneously analyze individual biomarkers of the patient and may use any number of pre-defined biomarker combinations. This method generally considers several parameters concerning the patient and/or the cancerous tissues and/or cells of the patient and does not classify the patient to a one-biomarker group, such as high or low PDL1 expression. Certain techniques described herein may be based on the simultaneous analysis of tens or hundreds of biomarkers.
- the techniques described herein provide a way to generate “thresholds” for pre-defined biomarkers based on (e.g., large volumes of) data obtained from large numbers of patients, such as TCGA, ICGC, Human Protein Atlas, etc., allowing for the creation of a normalized score for each of the biomarkers.
- Combinations of normalized biomarker scores for the patient may be used to analyze one more defined therapies (creating therapy scores) providing information that allows the selection of one or more therapies for each patient based on their personal parameters.
- biomarker refers to any information (or any parameter) of a biomolecule (e.g., a gene or a protein), a cancer (e.g., tumor type) or a subject (e.g., age of a subject) that may be used to predict an effect of a therapy or lack thereof in the subject.
- biomarker information or “biomarker value” as used herein, refers to any information relating to a biomarker. As a non-limiting example, if a biomarker is age, a biomarker value (e.g., information about the biomarker) may be 32 for a patient that is 32 years of age.
- a biomarker as described herein may be associated with at least one therapy and/or at least one cancer.
- the term “associated with” indicates that a biomarker has been found to be relevant (e.g., in one or more studies such as those described in a paper or journal article) to and/or involved with the associated therapy and/or the associated cancer.
- a biomarker in some embodiments, may be directly linked to a therapy and/or cancer or indirectly linked to a therapy and/or a cancer (e.g., that the biomarker has been found to directly or indirectly effect or modulate a biological process related to the therapy and/or the cancer).
- biomarkers for use with the methods and systems described herein may include any group or subset of biomarkers listed herein, including those listed in the Tables (e.g., in Table 2). Such a group or subset of biomarkers may include at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, or at least 1000 biomarkers.
- Such a group or subset of biomarkers may include up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 700, up to 800, up to 900, or up to 1000 biomarkers.
- a biomarker as described herein may be associated with multiple therapies.
- a biomarker may be associated with at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 different therapies.
- a biomarker may be associated with up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, or up to 100 different therapies.
- a biomarker as described herein may be associated with multiple cancers.
- a biomarker may be associated with at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 different cancers.
- a biomarker may be associated with up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, or up to 100 different cancers.
- Biomarkers as provided herein may be associated with any biomolecule.
- a biomolecule include, but are not limited to, a growth factor, a hormone, a steroid, a saccharide, a lipid, a heterocyclic compound, an elementary compound (e.g., iron), a metabolite, a vitamin, a neurotransmitter, and fatty acids.
- an elementary compound e.g., iron
- a metabolite e.g., iron
- a biomarker associated with a saccharide may be referred to as a saccharide biomarker
- a biomarker associated with a lipid may be referred to as a lipid biomarker
- a biomarker associated with a heterocyclic compound may be referred to as a heterocyclic biomarker
- a biomarker associated with an elementary compound may be referred to as an elementary compound biomarker.
- a “genetic biomarker,” as used herein, is a biomarker associated with a gene or any product thereof (e.g., RNA, protein).
- a genetic biomarker include, but are not limited to, a gene expression level (e.g., an increased expression level or a decreased expression level), a gene mutation, a gene insertion, a gene deletion, a gene fusion, a single nucleotide polymorphism (SNPs), and a gene copy number variation (CNV).
- genes are group by a related function and/or other property.
- gene groups include, but are not limited to, the fibroblasts group, the angiogenesis group, the tumor properties group, the anti-tumor immune microenvironment group, the tumor-promoting immune microenvironment group, the cancer associated fibroblasts group, the proliferation rate group, the PI3K/AKT/mTOR signaling group, the RAS/RAF/MEK signaling group, the receptor tyrosine kinases expression group, the tumor suppressors group, the metastasis signature group, the anti-metastatic factors group, the mutation status group, the antigen presentation group, the cytotoxic T and NK cells group, the B cells group, the anti-tumor microenvironment group, the checkpoint inhibition group, the Treg group, the MDSC group, the granulocytes group, the tumor-promotive immune group, the receptor tyrosine kinases expression group, the growth factors group
- a genetic biomarker may be associated with some (e.g., at least three) genes from one or more of the following groups: the fibroblasts group: LGALS1, COL1A1, COL1A2, COL4A1, COL5A1, TGFB1, TGFB2, TGFB3, ACTA2, FGF2, FAP, LRP1, CD248, COL6A1, COL6A2, and COL6A3; the angiogenesis group: VEGFA, VEGFB, VEGFC, PDGFC, CXCL8, CXCR2, FLT1, PIGF, CXCL5, KDR, ANGPT1, ANGPT2, TEK, VWF, CDH5, NOS3, KDR, VCAM1, MMRN1, LDHA, HIF1A, EPAS1, CA9, SPP1, LOX, SLC2A1, and LAMP3; the tumor properties group: MK167.
- the tumor properties group MK167.
- ESCO2 CETN3, CDK2, CCND1, CCNE1, AURKA, AURKB, CDK4, CDK6, PRC1, E2F1, MYBL2, BUB1, PLK1, CCNB1, MCM2, MCM6, PIK3CA, PIK3CB, PIK3CG, PIK3CD, AKT1, MTOR, PTEN, PRKCA, AKT2, AKT3, BRAF, FNTA, FNTB, MAP2K1, MAP2K2, MKNK1, MKNK2, ALK, AXL, KIT, EGFR, ERBB2, FLT3, MET, NTRK1, FGFR1, FGFR2, FGFR3, ERBB4, ERBB3, BCR-ABL, PDGFRA, PDGFRB, NGF, CSF3, CSF2, FGF7, IGF1, IGF2, IL7, FGF2, TP53, SIK1, PTEN, DCN, MTAP, AIM2, RB1, ESRP1, CTSL, HOX
- MAP2K2, MKNK1, and MKNK2 the receptor tyrosine kinases expression group: ALK, AXL, KIT, EGFR, ERBB2, FLT3, MET, NTRK1, FGFR1, FGFR2, FGFR3, ERBB4, ERBB3, BCR-ABL, PDGFRA, and PDGFRB; the tumor suppressors group: TP53, SIK1, PTEN, DCN, MTAP, AIM2, and RB1; the metastasis signature group: ESRP1, CTSL, HOXA1, SMARCA4, SNAI2, TWIST1, NEDD9, PAPPA, and HPSE; the anti-metastatic factors group: KISS1, ADGRG1, BRMS1, TCF21, CDH1, PCDH10, NCAM1, and MITF; the mutation status group: APC, ARID1A, ATM, ATRX, BAP1, BRAF, BRCA2, CDH1, CDKN2A, CTCF, CTNNB1,
- CD79A, CD79B, and BLK the anti-tumor microenvironment group: NOS2, IL12A, IL12B, IL23A, TNF, IL1B, SOCS3, IFNG, IL2, CD40LG, IL15, CD27, TBX21, LTA, IL21, HMGB1, TNF, IFNB1, IFNA2, CCL3, TNFSF10, and FASLG; the checkpoint inhibition group: PDCD1, CD274, CTLA4, LAG3, PDCD1LG2, BTLA, HAVCR2, and VSIR; the Treg group: CXCL12, TGFB1, TGFB2, TGFB3, FOXP3, CTLA4, IL10, TNFRSF1B, CCL17, CXCR4, CCR4, CCL22, CCL1, CCL2, CCL5, CXCL13, and CCL28; the MDSC group: IDO1, ARG1, IL4R, IL10, TGFB1, TGFB2, TGFB3, NO
- the metastasis signature group ESRP1, CTSL, HOXA1, SMARCA4, SNA12, TWIST1, NEDD9, PAPPA, and HPSE
- the anti-metastatic factors group KISS1, ADGRG1, BRMS1, TCF21, CDH1, PCDH10, NCAM1, and MITF
- the mutation status group APC, ARID1A, ATM, ATRX, BAP1, BRAF, BRCA2, CDH1, CDKN2A, CTCF, CTNNB1, DNMT3A, EGFR, FBXW7, FLT3, GATA3, HRAS, IDH1, KRAS, MAP3K1, MTOR, NAV3, NCOR1, NF1, NOTCH1, NPM1, NRAS, PBRM1, PIK3CA, PTK3R1, PTEN, RB1, RUNX1, SETD2, STAG2, TAF1, TP53, and VHL
- the MHCI group HLA-A,
- a “protein biomarker,” as used herein, is a biomarker associated with a protein.
- a protein biomarker include, but are not limited to, a protein expression level (e.g., an increased expression level or a decreased expression level), a protein activity level (e.g., an increased activity level or a decreased activity level), a protein mutation, and a protein truncation.
- a protein biomarker as described herein may associated with any protein.
- proteins related to protein biomarkers include, but are not limited to, interferons, cytotoxic proteins, enzymes, cell adhesion proteins, extracellular matrix proteins, transcription factor proteins, intracellular signaling proteins, cytokines, chemokines, chemokine receptors, and interleukins.
- biomarkers may be referred to by the biomolecule for which they are related to, for example, interferon biomarker, cytotoxic protein biomarker, enzyme biomarker, cell adhesion protein biomarker, extracellular matrix protein biomarker, transcription factor protein biomarker, intracellular signaling protein biomarker, cytokine biomarker, chemokine biomarker, chemokine receptor biomarker, and interleukin biomarker.
- protein biomarkers may include products of, for example, any of the genes listed or referred to herein.
- a “cellular biomarker,” as used herein, is a biomarker associated with a cell.
- Examples of cellular biomarkers include, but are not limited to, numbers of types of one or more cells, percentage of one or more types of cells, location of one or more cells, and structure or morphology of one or more cells.
- a cellular biomarker as described herein may be associated with any cell.
- cells include, but are not limited to, malignant cancer cells, leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- malignant cancer cells leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- MDSCs myeloid-derived suppressor cells
- an “expression biomarker,” as used herein, is a biomarker associated with an expression of a gene or a product thereof (e.g., RNA, protein).
- expression biomarkers include, but are not limited to, an increased expression level of a gene or product thereof, a decreased expression level of a gene or product thereof, expression of a truncated gene or product thereof, and expression of a mutated gene or product thereof.
- the expression level of a biomarker in a sample obtained from a subject By comparing the expression level of a biomarker in a sample obtained from a subject to a reference (or control), it can be determined whether the subject has an altered expression level (e.g., increased or decreased) as compared to the reference (or control). For example, if the level of a biomarker in a sample from a subject deviates (e.g., is increased or decreased) from the reference value (by e.g., 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or more from a reference value), the biomarker might be identified as an expression biomarker.
- imaging biomarker is a biomarker associated with imaging data.
- imaging biomarkers include, but are not limited to, expression levels obtained from imaging data, numbers of types of one or more cells obtained from imaging data, and cancer location and/or progression obtained from imaging data.
- An imaging biomarker as described herein may be associated with any imaging data.
- imaging data include, but are not limited to, histological imaging data, immunohistological imaging data, magnetic resonance imaging (MRI) data, ultrasound data, and x-ray data.
- MRI magnetic resonance imaging
- a “disease-state biomarker,” as used herein, is a biomarker associated with a state of a disease (e.g., cancer).
- diseases-state biomarkers include, but are not limited to, metastasis status (e.g., absence or presence of metastasis), remission status (e.g., number of previous remissions, current remission), disease progression (e.g., low, moderate, or high disease progression), and cancer stage (e.g., stage 1 , stage 2 , stage 3 , or stage 4 ).
- Biomarkers as used herein encompasses any patient specific information that may be used to predict that patient's response to a therapy. For example, a personal habit of a patient (e.g., smoking) may be used as a biomarker to predict whether the patient is a responder or non-responder to a therapy.
- a personal habit of a patient e.g., smoking
- a biomarker may be used as a biomarker to predict whether the patient is a responder or non-responder to a therapy.
- a “personal habit biomarker,” as used herein, is a biomarker associated with a personal habit of a subject.
- Examples of personal habit biomarkers include, but are not limited to, smoking (e.g., status as a smoker or non-smoker), frequency of exercise, alcohol use (e.g., low, moderate, high use of alcohol), and drug use (e.g., low, moderate, high use of drugs).
- a cultural or environmental factor experienced by a patient may play a role in whether the patient responds to a therapy.
- Such factors are used in systems and methods described herein to predict a patient's response to a therapy.
- anthropological biomarker is a biomarker associated with a culture and/or an environment of a subject.
- anthropological biomarkers include, but are not limited to, stress (e.g., low, moderate, or high stress levels), economic status (e.g., low, moderate, or high economic status), mental health (e.g., depression or anxiety), and relationship status (e.g., married, single, divorced, or widowed).
- aspects of the present disclosure provide systems and methods that normalize biomarker scores to a common scale, thereby allowing comparison of biomarker scores across different cell populations and/or among different subjects.
- Normalized biomarker scores may be determined for any number of biomarkers as described herein.
- the term “normalized biomarker score” refers to a biomarker value that has been adjusted (e.g., normalized) to a common scale according to the techniques described herein.
- biomarker values are normalized to create normalized biomarker scores based on a respective distribution of values for each biomarker in a reference subset of biomarkers.
- the reference subset of biomarkers comprises biomarker information from any number of reference subjects.
- a “reference subset” is a subset of biomarkers from one or more reference subjects, the values of which may be used to normalize a biomarker of a subject.
- data may be available for up to 4,000 biomarkers for a group of subjects.
- 1,000 biomarkers may be associated with a particular therapy (thus creating a reference subset of 1,000 biomarkers). If, for a particular subject being analyzed using the methods and systems described herein, values for 723 of these biomarkers are available (thus creating a subject subset of 723 biomarkers), a normalized biomarker score for each of the 723 biomarkers may be computed using the distribution of values for each particular biomarker.
- 10 biomarkers may be associated with a particular therapy (thus creating a reference subset of 10 biomarkers).
- a normalized biomarker score for each of the 7 biomarkers may be computed using the distribution of values for each particular biomarker.
- the reference subset of biomarkers comprises biomarker information from any number of subjects.
- the reference subset of biomarkers comprises biomarker information from at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 subjects.
- the reference subset of biomarkers comprises biomarker information from up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 subjects.
- a reference subset of biomarkers may comprise any number of biomarkers.
- the reference subset of biomarkers comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 biomarkers.
- the reference subset of biomarkers comprises up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 biomarkers.
- biomarker values are normalized to create normalized biomarker scores based on a respective distribution of values for each biomarker in a subject subset of biomarkers.
- the “subject subset” of biomarkers comprises biomarker information from a single subject.
- a subject subset of biomarkers may comprise any number of biomarkers.
- the subject subset of biomarkers comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 biomarkers.
- the subject subset of biomarkers comprises up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 biomarkers.
- the subject subset of biomarkers is identical to the reference subset of biomarkers (i.e., for a given calculation, system, or method described herein).
- systems and methods described herein provide for determining any number of normalized biomarker scores using sequencing data and biomarker information.
- systems and methods described herein provide for determining at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 normalized biomarker scores.
- systems and methods described herein provide for determining up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 normalized biomarker scores.
- systems and methods described herein provide for determining normalized biomarker scores for biomarkers associated with a particular therapy.
- systems and methods described herein provide for determining normalized biomarker scores for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 biomarkers associated with a particular therapy.
- systems and methods described herein provide for determining normalized biomarker scores for up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 biomarkers associated with a particular therapy.
- Systems and methods for normalization of biomarkers as described herein may be applied to biomarkers for any cancer (e.g., any tumor).
- exemplary cancers include, but are not limited to, adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, colon adenocarcinoma, esophageal carcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, thyroid carcinoma, uterine corpus endometrial carcinoma, any type of lymphoma, leukemia, and cholangiocarcinoma.
- Biomarker information as described herein may be obtained from a variety of sources.
- biomarker information may be obtained by analyzing a biological sample from a patient. The biological sample may be analyzed prior to performance of the methods described herein for predicting the efficacy of one or more treatments for the patient.
- data obtained from the biological sample may stored (e.g., in a database) and accessed during performance of the techniques described herein for predicting the efficacy of one or more treatments for the patient.
- biomarker information is obtained from a database containing biomarker information for at least one patient.
- any biological sample from a subject may be analyzed as described herein to obtain biomarker information.
- the biological sample may be any sample from a subject known or suspected of having cancerous cells or pre-cancerous cells.
- the biological sample may be from any source in the subject's body including, but not limited to, any fluid [such as blood (e.g., whole blood, blood serum, or blood plasma), saliva, tears, synovial fluid, cerebrospinal fluid, pleural fluid, pericardial fluid, ascitic fluid, and/or urine], hair, skin (including portions of the epidermis, dermis, and/or hypodermis), oropharynx, laryngopharynx, esophagus, stomach, bronchus, salivary gland, tongue, oral cavity, nasal cavity, vaginal cavity, anal cavity, bone, bone marrow, brain, thymus, spleen, small intestine, appendix, colon, rectum, anus, liver, biliary tract, pancreas, kidney, ureter, bladder, urethra, uterus, vagina, vulva, ovary, cervix, scrotum, penis, prostate, testicle,
- the biological sample may be any type of sample including, for example, a sample of a bodily fluid, one or more cells, a piece of tissue, or some or all of an organ.
- one sample will be taken from a subject for analysis.
- more than one e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more
- samples may be taken from a subject for analysis.
- one sample from a subject will be analyzed.
- more than one (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more) samples may be analyzed.
- the samples may be procured at the same time (e.g., more than one sample may be taken in the same procedure), or the samples may be taken at different times (e.g., during a different procedure including a procedure 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 months, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 years, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 decades after a first procedure).
- a second or subsequent sample may be taken or obtained from the same region (e.g., from the same tumor or area of tissue) or a different region (including, e.g., a different tumor).
- a second or subsequent sample may be taken or obtained from the subject after one or more treatments, and may be taken from the same region or a different region.
- the second or subsequent sample may be useful in determining whether the cancer in each sample has different characteristics (e.g., in the case of samples taken from two physically separate tumors in a patient) or whether the cancer has responded to one or more treatments (e.g., in the case of two or more samples from the same tumor or different tumors prior to and subsequent to a treatment).
- the biological sample described herein may be obtained from the subject using any known technique.
- the biological sample may be obtained from a surgical procedure (e.g., laparoscopic surgery, microscopically controlled surgery, or endoscopy), bone marrow biopsy, punch biopsy, endoscopic biopsy, or needle biopsy (e.g., a fine-needle aspiration, core needle biopsy, vacuum-assisted biopsy, or image-guided biopsy).
- each of the at least one biological samples is a bodily fluid sample, a cell sample, or a tissue biopsy.
- one or more than one cell may be obtained from a subject using a scrape or brush method.
- the cell sample may be obtained from any area in or from the body of a subject including, for example, from one or more of the following areas: the cervix, esophagus, stomach, bronchus, or oral cavity.
- one or more than one piece of tissue e.g., a tissue biopsy
- the tissue biopsy may comprise one or more than one (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10) samples from one or more tumors or tissues known or suspected of having cancerous cells.
- Systems and methods described herein are based, at least in part, on the identification and characterization of certain biomarkers of a patient and/or the patient's cancer. Such information may be obtained from a biological sample of the subject (e.g., the patient) as described herein.
- a biological sample from a subject Any type of analysis may be performed on a biological sample from a subject.
- a blood analysis is performed on a biological sample from a subject.
- a cytometry analysis is performed on a biological sample from a subject.
- a histological analysis is performed on a biological sample from a subject.
- a immunohistological analysis is performed on a biological sample from a subject.
- sequencing data may be obtained from a biological sample of a subject.
- the sequencing data is DNA sequencing data.
- the sequencing data is RNA sequencing data.
- the sequencing data is proteome sequencing data.
- the sequencing data is obtained by any known technique.
- the sequencing data is obtained from whole genome sequencing (WGS).
- the sequencing data is obtained from whole exome sequencing (WES).
- the sequencing data is obtained from whole transcriptome sequencing.
- the sequencing data is obtained from mRNA sequencing.
- the sequencing data is obtained from DNA/RNA-hybridization.
- the sequencing data is obtained from microarray.
- the sequencing data is obtained from DNA/RNA chip.
- the sequencing data is obtained from PCR.
- the sequencing data is obtained from single nucleotide polymorphism (SNP) genotyping.
- SNP single nucleotide polymorphism
- Expression data e.g., indicating expression levels
- a plurality of genes may be obtained from a biological sample. There is no limit to the number of genes which may be examined. For example, there is no limit to the number of genes for which the expression levels may be examined.
- At least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, or at least 300 genes may be used for any evaluation described herein.
- up to four, up to five, up to six, up to seven, up to eight, up to nine, up to ten, up to eleven, up to twelve, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 21, up to 22, up to 23, up to 24, up to 25, up to 26, up to 27, up to 28, up to 29, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, up to 100, up to 125, up to 150, up to 175, up to 200, up to 225, up to 250, up to 275, or up to 300 genes may be used for any evaluation described herein.
- any method may be used on a sample from a subject in order to acquire expression data (e.g., indicating expression levels) for the plurality of genes.
- the expression data may be RNA expression data, DNA expression data, or protein expression data.
- DNA expression data refers to a level of DNA in a sample from a subject.
- the level of DNA in a sample from a subject having cancer may be elevated compared to the level of DNA in a sample from a subject not having cancer, e.g., a gene duplication in a cancer patient's sample.
- the level of DNA in a sample from a subject having cancer may be reduced compared to the level of DNA in a sample from a subject not having cancer, e.g., a gene deletion in a cancer patient's sample.
- DNA expression data refers to data for DNA (or gene) expressed in a sample, for example, sequencing data for a gene that is expressed in a patient's sample. Such data may be useful, in some embodiments, to determine whether the patient has one or more mutations associated with a particular cancer.
- RNA expression data may be acquired using any method known in the art including, but not limited to: whole transcriptome sequencing, total RNA sequencing, mRNA sequencing, targeted RNA sequencing, small RNA sequencing, ribosome profiling, RNA exome capture sequencing, and/or deep RNA sequencing.
- DNA expression data may be acquired using any method known in the art including any known method of DNA sequencing.
- DNA sequencing may be used to identify one or more mutations in the DNA of a subject. Any technique used in the art to sequence DNA may be used with the methods and systems described herein.
- the DNA may be sequenced through single-molecule real-time sequencing, ion torrent sequencing, pyrosequencing, sequencing by synthesis, sequencing by ligation (SOLiD sequencing), nanopore sequencing, or Sanger sequencing (chain termination sequencing).
- Protein expression data may be acquired using any method known in the art including, but not limited to: N-terminal amino acid analysis, C-terminal amino acid analysis, Edman degradation (including though use of a machine such as a protein sequenator), or mass spectrometry.
- the expression data comprises whole exome sequencing (WES) data. In some embodiments, the expression data comprises whole genome sequencing (WGS) data. In some embodiments, the expression data comprises next-generation sequencing (NGS) data. In some embodiments, the expression data comprises microarray data.
- biomarker information may be obtained from one or more databases and/or any other suitable electronic repository of data. Examples of databases include, but are not limited to, CGP (Cancer Genome Project), CPTAC (Clinical Proteomic Tumor Analysis Consortium), ICGC (International Cancer Genome Consortium), and TCGA (The Cancer Genome Atlas).
- biomarker information may be obtained from data associated with a clinical trial.
- biomarker information may be predicted in association with a clinical trial based on one or more similar drugs (e.g., drugs of a similar class such as PD-1 inhibitors).
- biomarker information may be obtained from a hospital database. In some embodiments, biomarker information may be obtained from a commercial sequencing supplier. In some embodiments, biomarker information may be obtained from a subject (e.g., a patient) and/or a subject's (e.g., a patient's) relative, guardian, or caretaker.
- a subject e.g., a patient
- a subject's e.g., a patient's
- Expression data includes gene expression levels. Gene expression levels may be detected by detecting a product of gene expression such as mRNA and/or protein.
- gene expression levels are determined by detecting a level of a protein in a sample and/or by detecting a level of activity of a protein in a sample.
- the terms “determining” or “detecting” may include assessing the presence, absence, quantity and/or amount (which can be an effective amount) of a substance within a sample, including the derivation of qualitative or quantitative concentration levels of such substances, or otherwise evaluating the values and/or categorization of such substances in a sample from a subject.
- the level of a protein may be measured using an immunoassay.
- immunoassays include any known assay (without limitation), and may include any of the following: immunoblotting assay (e.g., Western blot), immunohistochemical analysis, flow cytometry assay, immunofluorescence assay (IF), enzyme linked immunosorbent assays (ELISAs) (e.g., sandwich ELISAs), radioimmunoassays, electrochemiluminescence-based detection assays, magnetic immunoassays, lateral flow assays, and related techniques. Additional suitable immunoassays for detecting a level of a protein provided herein will be apparent to those of skill in the art.
- Such immunoassays may involve the use of an agent (e.g., an antibody) specific to the target protein.
- an agent such as an antibody that “specifically binds” to a target protein is a term well understood in the art, and methods to determine such specific binding are also well known in the art.
- An antibody is said to exhibit “specific binding” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular target protein than it does with alternative proteins. It is also understood by reading this definition that, for example, an antibody that specifically binds to a first target peptide may or may not specifically or preferentially bind to a second target peptide.
- binding does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding.
- an antibody that “specifically binds” to a target peptide or an epitope thereof may not bind to other peptides or other epitopes in the same antigen.
- a sample may be contacted, simultaneously or sequentially, with more than one binding agent that binds different proteins (e.g., multiplexed analysis).
- an antibody refers to a protein that includes at least one immunoglobulin variable domain or immunoglobulin variable domain sequence.
- an antibody can include a heavy (H) chain variable region (abbreviated herein as VH), and a light (L) chain variable region (abbreviated herein as VL).
- VH heavy chain variable region
- L light chain variable region
- an antibody includes two heavy (H) chain variable regions and two light (L) chain variable regions.
- antibody encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab and sFab fragments, F(ab′)2, Fd fragments, Fv fragments, scFv, and domain antibodies (dAb) fragments (de Wildt et al., Eur J Immunol. 1996; 26(3):629-39.)) as well as complete antibodies.
- An antibody can have the structural features of IgA, IgG, IgE, IgD, IgM (as well as subtypes thereof).
- Antibodies may be from any source including, but not limited to, primate (human and non-human primate) and primatized (such as humanized) antibodies.
- the antibodies as described herein can be conjugated to a detectable label and the binding of the detection reagent to the peptide of interest can be determined based on the intensity of the signal released from the detectable label.
- a secondary antibody specific to the detection reagent can be used.
- One or more antibodies may be coupled to a detectable label. Any suitable label known in the art can be used in the assay methods described herein.
- a detectable label comprises a fluorophore.
- fluorophore also referred to as “fluorescent label” or “fluorescent dye” refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength.
- a detection moiety is or comprises an enzyme.
- an enzyme is one (e.g., ⁇ -galactosidase) that produces a colored product from a colorless substrate.
- Detection assays that are not based on an antibody, such as mass spectrometry, are also useful for the detection and/or quantification of a protein and/or a level of protein as provided herein.
- Assays that rely on a chromogenic substrate can also be useful for the detection and/or quantification of a protein and/or a level of protein as provided herein.
- the level of nucleic acids encoding a gene in a sample can be measured via a conventional method.
- measuring the expression level of nucleic acid encoding the gene comprises measuring mRNA.
- the expression level of mRNA encoding a gene can be measured using real-time reverse transcriptase (RT) Q-PCR or a nucleic acid microarray.
- RT real-time reverse transcriptase
- Methods to detect nucleic acid sequences include, but are not limited to, polymerase chain reaction (PCR), reverse transcriptase-PCR (RT-PCR), in situ PCR, quantitative PCR (Q-PCR), real-time quantitative PCR (RT Q-PCR), in situ hybridization, Southern blot, Northern blot, sequence analysis, microarray analysis, detection of a reporter gene, or other DNA/RNA hybridization platforms.
- PCR polymerase chain reaction
- RT-PCR reverse transcriptase-PCR
- Q-PCR quantitative PCR
- RT Q-PCR real-time quantitative PCR
- in situ hybridization Southern blot, Northern blot, sequence analysis, microarray analysis, detection of a reporter gene, or other DNA/RNA hybridization platforms.
- the level of nucleic acids encoding a gene in a sample can be measured via a hybridization assay.
- the hybridization assay comprises at least one binding partner.
- the hybridization assay comprises at least one oligonucleotide binding partner.
- the hybridization assay comprises at least one labeled oligonucleotide binding partner.
- the hybridization assay comprises at least one pair of oligonucleotide binding partners.
- the hybridization assay comprises at least one pair of labeled oligonucleotide binding partners.
- binding agent that specifically binds to a desired nucleic acid or protein may be used in the methods and kits described herein to measure an expression level in a sample.
- the binding agent is an antibody or an aptamer that specifically binds to a desired protein.
- the binding agent may be one or more oligonucleotides complementary to a nucleic acid or a portion thereof.
- a sample may be contacted, simultaneously or sequentially, with more than one binding agent that binds different proteins or different nucleic acids (e.g., multiplexed analysis).
- a sample can be in contact with a binding agent under suitable conditions.
- the term “contact” refers to an exposure of the binding agent with the sample or cells collected therefrom for suitable period sufficient for the formation of complexes between the binding agent and the target protein or target nucleic acid in the sample, if any.
- the contacting is performed by capillary action in which a sample is moved across a surface of the support membrane.
- an assay may be performed in a low-throughput platform, including single assay format. In some embodiments, an assay may be performed in a high-throughput platform.
- Such high-throughput assays may comprise using a binding agent immobilized to a solid support (e.g., one or more chips). Methods for immobilizing a binding agent will depend on factors such as the nature of the binding agent and the material of the solid support and may require particular buffers. Such methods will be evident to one of ordinary skill in the art.
- the various genes recited herein are, in general, named using human gene naming conventions.
- the various genes are described in publically available resources such as published journal articles.
- the gene names may be correlated with additional information (including sequence information) through use of, for example, the NCBI GenBank® databases available at www ⁇ dot>ncbi ⁇ dot>nlm ⁇ dot>nih ⁇ dot>gov; the HUGO (Human Genome Organization) Gene Nomination Committee (HGNC) databases available at www ⁇ dot>genenames ⁇ dot>org; the DAVID Bioinformatics Resource available at www ⁇ dot>david ⁇ dot>ncifcrf ⁇ dot>gov.
- a gene may encompass all variants of that gene.
- specific-specific genes may be used. Synonyms, equivalents, and closely related genes (including genes from other organisms) may be identified using similar databases including the NCBI GenBank® databases described above.
- Normalized biomarker scores derived from a patient and/or a patient's biological sample as described herein may be used for various clinical purposes including, for example, identifying subjects suitable for a particular treatment (e.g., an immunotherapy), and/or predicting likelihood of a patient's response or lack thereof to a particular treatment. Accordingly, described herein are prognostic methods for predicting therapy efficacy, for example, an immunotherapy, based on a patient's biomarker values.
- the systems and methods described herein may be used to predict whether a patient (subject) may or may not have one or more adverse reactions to a particular therapy, based on the patient's biomarker values (e.g., whether a subject is likely to have immune-mediated adverse reactions to checkpoint blockade therapy and/or not have immune-mediated adverse reactions to checkpoint blockade therapy).
- a therapy score for a patient may be determined for a particular therapy.
- the term “therapy score” is calculated using multiple normalized biomarker scores for a patient that is indicative of a predicted response of that subject to a therapy.
- such a “therapy score” may be calculated using multiple normalized biomarker scores in one or more of the following ways: 1) as a sum; 2) as a weighted sum (e.g., in a regression model); 3) using any linear or generalized linear model taking the normalized biomarker scores as inputs and producing, based on the input normalized biomarker scores, an output indicative of a patient's predicted response to a therapy; 4) using any statistical model (e.g., a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a support vector regression model, a Gaussian mixture model, random forest regression, and/or any other suitable type mixture model) taking the normalized biomarker scores as inputs and producing, based on the input biomarker scores, an output indicative of a patient's predicted response to a therapy.
- any statistical model e.g., a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a support vector regression model, a Gaus
- a therapy score as described herein includes a therapy score calculated using any suitable number of normalized biomarker scores.
- the therapy score may be calculated using at least 2 normalized biomarker scores.
- the therapy score may be calculated using at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 normalized biomarker scores.
- a therapy score is calculated using one or more normalized biomarker values which may be weighted by one or more respective weights as part of the calculation.
- a biomarker weight may be assigned to any biomarker. For example, an abundant biomarker may be assigned a higher weight for predicting a therapy response.
- Such weights may be determined, for example, using a machine learning technique. As a non-limiting set of examples, such weights may be determined by training a regression model (e.g., a linear regression model, a generalized linear model, a support vector regression model, a logistic regression model, a random forest regression model, a neural network model, etc.).
- a regression model e.g., a linear regression model, a generalized linear model, a support vector regression model, a logistic regression model, a random forest regression model, a neural network model, etc.
- a therapy score for a therapy may be a positive value or a negative value.
- a positive therapy score in some embodiments, is indicative of a positive response to a therapy.
- a negative therapy score in some embodiments, is indicative of a negative response or no response to a therapy.
- a therapy score close to zero in some embodiments, is indicative of little or no measurable response to a therapy.
- a therapy score in some embodiments, more accurately predicts a patient's response to a therapy when compared, for example, to using a single biomarker.
- a patient's response to a therapy may be more accurately predicted as a therapy score positively increases in numeric value.
- a patient's lack of response to a therapy may be more accurately predicted as a therapy score negatively increases in numeric value.
- the terms “subject” or “patient” may be used interchangeably and refer to a subject who needs the analysis as described herein.
- the subject is a human or a non-human mammal (e.g., a non-human primate).
- the subject is suspected to have cancer or is at risk for cancer.
- the subject has (e.g., is known to have) cancer.
- cancer examples include, without limitation, adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, colon adenocarcinoma, esophageal carcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, thyroid carcinoma, uterine corpus endometrial carcinoma, one or more types of leukemia, and cholangiocarcinoma.
- the subject is a human patient having one or more symptom of a cancer.
- the subject may have fatigue, pain, weakness or numbness, loss of bladder or bowl control, cough, blood-tinged saliva, anemia, breast lump or discharge, or a combination thereof.
- the subject has a symptom of cancer or has a history of a symptom of cancer.
- the subject has more than one symptom of cancer or has a history of more than one symptoms of cancer.
- the subject has no symptom of cancer, has no history of a symptom of cancer, or has no history of cancer.
- Such a subject may exhibit one or more symptoms associated with a cancer.
- a subject may have one or more risk factors for cancer, for example, an environmental factor associated with cancer (e.g., geographic location or exposure to a mutagen), a family history of cancer, and/or a genetic predisposition to developing cancer.
- the subject who needs the analysis described herein may be a patient having cancer or suspected of having cancer.
- a subject may currently be having a relapse, or may have suffered from the disease in the past (e.g., may be currently relapse-free), or may have cancer.
- the subject is a human patient who may be on a treatment (i.e., the subject may be receiving treatment) for the disease including, for example, a treatment involving chemotherapy or radiation therapy. In other instances, such a human patient may be free of such a treatment.
- the systems and methods described herein may be used to assess the effectiveness of a therapy over time.
- aspects of the disclosure provide methods and systems for using normalized biomarker scores obtained from samples prior to and subsequent to administration of a candidate therapy to determine the efficacy of that therapy.
- such methods may also be used to select a candidate therapy for use with a patient or subject.
- such methods may be used to assess the impact of a candidate therapy, which impact may be quantified by determining an impact score, in accordance with some embodiments described herein.
- some embodiments provide for determining, using a first and second set of normalized biomarker scores for a subject, an impact score for a candidate therapy, wherein the first and second set of normalized biomarker scores are determined using first sequencing data about at least one biological sample of a subject prior to administration of the candidate therapy, and second sequencing data about at least one biological sample of a subject subsequent to administration of the candidate therapy.
- an impact score would be indicative of response (e.g., a positive or negative response) of the subject to administration of the candidate therapy.
- aspects of the disclosure provide computer implemented methods for determining, using a set of normalized biomarker scores, biomarker scores for a subject indicative of a patient's response or lack thereof to a particular therapy.
- a software program may provide a user with a visual representation presenting information related to a patient's biomarkers scores (e.g., a biomarker score, and/or a therapy score, and/or an impact score), and predicted efficacy of a therapy.
- a software program may execute in any suitable computing environment including, but not limited to, a cloud-computing environment, a device co-located with a user (e.g., the user's laptop, desktop, smartphone, etc.), one or more devices remote from the user (e.g., one or more servers), etc.
- the techniques described herein may be implemented in the illustrative environment 100 shown in FIG. 1 A .
- one or more biological samples of a patient 102 may be provided to a laboratory 104 .
- Laboratory 104 may process the biological sample(s) to obtain sequencing data (e.g., transcriptome, exome, and/or genome sequencing data) and provide it, via network 108 , to at least one database 106 that stores information about patient 102 .
- sequencing data e.g., transcriptome, exome, and/or genome sequencing data
- Network 108 may be a wide area network (e.g., the Internet), a local area network (e.g., a corporate Intranet), and/or any other suitable type of network. Any of the devices shown in FIG. 1 A may connect to the network 108 using one or more wired links, one or more wireless links, and/or any suitable combination thereof.
- a wide area network e.g., the Internet
- a local area network e.g., a corporate Intranet
- Any of the devices shown in FIG. 1 A may connect to the network 108 using one or more wired links, one or more wireless links, and/or any suitable combination thereof.
- the at least one database 106 may store sequencing data for the patient, expression data for the patient, medical history data for the patient, test result data for the patient, and/or any other suitable information about the patient 102 .
- Examples of stored test result data for the patient include biopsy test results, imaging test results (e.g., MRI results), and blood test results.
- the information stored in at least one database 106 may be stored in any suitable format and/or using any suitable data structure(s), as aspects of the technology described herein are not limited in this respect.
- the at least one database 106 may store data in any suitable way (e.g., one or more databases, one or more files).
- the at least one database 106 may be a single database or multiple databases.
- illustrative environment 100 includes one or more external databases 116 , which may store information for patients other than patient 102 .
- external databases 116 may store expression data (of any suitable type) for one or more patients, medical history data for one or more patients, test result data (e.g., imaging results, biopsy results, blood test results) for one or more patients, demographic and/or biographic information for one or more patients, and/or any other suitable type of information.
- external database(s) 116 may store information available in one or more publically accessible databases such as TCGA (The Cancer Genome Atlas), one or more databases of clinical trial information, and/or one or more databases maintained by commercial sequencing suppliers.
- the external database(s) 116 may store such information in any suitable way using any suitable hardware, as aspects of the technology described herein are not limited in this respect.
- the at least one database 106 and the external database(s) 116 may be the same database, may be part of the same database system, or may be physically co-located, as aspects of the technology described herein are not limited in this respect.
- information stored in patient information database 106 and/or in external database(s) 116 may be used to perform any of the techniques described herein related to determining a therapy score and/or impact score indicative of a patient's response to a therapy.
- the information stored in the database(s) 106 and/or 116 may be accessed, via network 108 , by software executing on server(s) 110 to perform any one or more of the techniques described herein in connection with FIGS. 2 A, 2 B, 2 C, 2 D and 2 E .
- server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform process 200 , described with reference to FIG. 2 A , for determining therapy scores for multiple therapies based on normalized biomarker scores.
- server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform process 220 , described with reference to FIG. 2 B , for determining the effectiveness of a candidate therapy on a patient.
- server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform process 240 , described with reference to FIG. 2 C , for determining therapy scores for at least two selected therapies based on normalized biomarker scores for at least three biomarkers for each of the therapies.
- server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform process 260 , described with reference to FIG. 2 D , for obtaining first and second therapy scores for first and second therapies.
- server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform process 280 , described with reference to FIG. 2 E , for identifying a subject as a member of a cohort using normalized biomarker scores.
- server(s) 110 may include one or multiple computing devices. When server(s) 110 include multiple computing devices, the device(s) may be physically co-located (e.g., in a single room) or distributed across multi-physical locations. In some embodiments, server(s) 110 may be part of a cloud computing infrastructure. In some embodiments, one or more server(s) 110 may be co-located in a facility operated by an entity (e.g., a hospital, research institution) with which doctor 114 is affiliated. In such embodiments, it may be easier to allow server(s) 110 to access private medical data for the patient 102 .
- entity e.g., a hospital, research institution
- the results of the analysis performed by server(s) 110 may be provided to doctor 114 through a computing device 114 (which may be a portable computing device, such as a laptop or smartphone, or a fixed computing device such as a desktop computer).
- the results may be provided in a written report, an e-mail, a graphical user interface, and/or any other suitable way.
- the results may be provided to patient 102 or a caretaker of patient 102 , a healthcare provider such as a nurse, or a person involved with a clinical trial.
- the results may be part of a graphical user interface (GUI) presented to the doctor 114 via the computing device 112 .
- GUI graphical user interface
- the GUI may be presented to the user as part of a webpage displayed by a web browser executing on the computing device 112 .
- the GUI may be presented to the user using an application program (different from a web-browser) executing on the computing device 112 .
- the computing device 112 may be a mobile device (e.g., a smartphone) and the GUI may be presented to the user via an application program (e.g., “an app”) executing on the mobile device.
- an application program e.g., “an app”
- the GUI presented on computing device 112 provides a wide range of oncological data relating to both the patient and the patient's cancer in a new way that is compact and highly informative.
- oncological data was obtained from multiple sources of data and at multiple times making the process of obtaining such information costly from both a time and financial perspective.
- a user can access the same amount of information at once with less demand on the user and with less demand on the computing resources needed to provide such information.
- Low demand on the user serves to reduce clinician errors associated with searching various sources of information.
- Low demand on the computing resources serves to reduce processor power, network bandwidth, and memory needed to provide a wide range of oncological data, which is an improvement in computing technology.
- FIG. 1 B shows a block diagram of an illustrative GUI 150 containing information about patient 102 .
- GUI 150 may include separate portions providing different types of information about patient 102 .
- Illustrative GUI 150 includes the following portions: Patient Information Portion 152 , Molecular-Functional (MF) Portrait Portion 160 , Clinical Trial Information Portion 162 , Immunotherapy Portion 154 , Efficacy Predictor Portion 156 , and Targeted Therapy Selection Portion 158 .
- MF Molecular-Functional
- Patient Information Portion 152 may provide general information about the patient and the patient's cancer.
- General information about the patient may include such information as the patient's name and date of birth, the patient's insurance provider, and contact information for the patient such as address and phone number.
- General information about the patient's cancer may include the patient's diagnosis, the patient's history of relapse and/or remission, and information relating to stage of the patient's cancer.
- Patient Information Portion 152 may also provide information relating to potential treatment options for the patient and/or previously administered treatments.
- Molecular-Functional (MF) Portrait Portion 160 may include a molecular functional tumor portrait (MF profile) which refers to a graphical depiction of a tumor with regard to its molecular and cellular composition, and biological processes that are present within and/or surrounding the tumor. Further aspects relating to a patient's MF profile are provided in International patent application number PCT/US18/37017, entitled “Systems and Methods for Generating, Visualizing and Classifying Molecular Functional Profiles,” filed Jun. 12, 2018, the entire contents of which are incorporated herein by reference.
- MF profile molecular functional tumor portrait
- PCT/US18/37017 entitled “Systems and Methods for Generating, Visualizing and Classifying Molecular Functional Profiles,” filed Jun. 12, 2018, the entire contents of which are incorporated herein by reference.
- Clinical Trial Information Portion 162 may include information relating to a clinical trial for a therapy that may be and/or will be administered to the patient.
- Clinical Trial Information Portion 162 may provide information about an ongoing clinical trial or a completed clinical trial.
- Information that may be provided in Clinical Trial Information Portion 162 may include information related to a therapy used in the clinical trial such as dosage and dosage regimen, number and diagnosis of patients participating in the clinical trial, and patient outcomes.
- Immunotherapy Portion 154 may include patient specific information as it relates to an immunotherapy. Immunotherapy Portion 154 may provide such information for different immunotherapies, for example, immune checkpoint blockade therapies, anti-cancer vaccine therapies, and T cell therapies.
- Patient specific information relating to an immunotherapy may include information about the patient such as the patient's biomarkers associated with an immunotherapy and/or information about the patient's cancer such as composition of immune cells in the patient's tumor.
- Efficacy Predictor Portion 156 may include information indicative of the patient's predicted response to an immunotherapy based on patient specific information presented in Immunotherapy Portion 154 . Efficacy Predictor Portion 156 may provide predicted efficacy of an immunotherapy determined, in some embodiments, using a patient's biomarkers as described in herein. Additionally or alternatively, Efficacy Predictor Portion 156 may provide predicted efficacy of an immune checkpoint blockade therapy determined using patient specific information such as gene expression data as described in International patent application number PCT/US18/37018, entitled “Systems and Methods for Identifying Responders and Non-Responders to Immune Checkpoint Blockade Therapy,” filed Jun. 12, 2018, the entire contents of which are incorporated herein by reference.
- Targeted Therapy Selection Portion 158 may include patient specific information as it relates to a targeted therapy. Targeted Therapy Selection Portion 158 may provide such information for different targeted therapies, for example, a kinase inhibitor therapy, a chemotherapy, and anti-cancer antibody therapy.
- Patient specific information relating to an a targeted therapy may include information about the patient such as the patient's biomarkers associated with a targeted therapy and/or information about the patient's cancer such as whether a mutation is present in the patient's tumor.
- Patient Information Portion 172 may provide different information in different panels, for example, Overall Status panel, Disease Characteristics panel, and General Recommendations panel.
- Overall Status panel in some embodiments, may provide general information about the patient such as patient name and patient age.
- Disease Characteristics panel in some embodiments, may provide information about the patient's cancer such as type of cancer and stage of cancer.
- General Recommendations panel in some embodiments, may provide previous treatments and possible treatment options for the patient.
- Clinical Trial Information Portion 182 a provides information relating to a clinical trial for anti-PD1 therapy.
- Clinical Trial Information Portion 182 a (as shown in the upper portion) shows a graph providing patient overall response rate (ORR) for anti-PD1 therapy and other therapies such as vaccine or IFN ⁇ therapies.
- ORR patient overall response rate
- a user may select portions of the Clinical Trial Information Portion 182 a to access information related to patient progression-free survival (PFS) and/or patient overall survival (OS).
- Clinical Trial Information Portion 182 a (as shown in the lower portion) provides information relating to different clinical trials that may be presented to a user including a brief description of the clinical trial.
- Clinical Trial Information Portion 182 b provides information relating to a clinical trial for different targeted therapies.
- Clinical Trial Information Portion 182 b (as shown in the upper portion) shows a graph providing patient overall response rate (ORR) for different targeted therapies including sunitinib (SU), imatinib (IM), vemurafenib (VER) and dabrafenib (DAB).
- ORR patient overall response rate
- a user may select portions of the Clinical Trial Information Portion 182 b to access information related to patient progression-free survival (PFS) and/or patient overall survival (OS).
- Clinical Trial Information Portion 182 b (as shown in the lower portion) provides information relating to different clinical trials that may be presented to a user including a brief description of the clinical trial.
- Immunotherapy Portion 174 provides patient specific information associated with an immunotherapy and information indicative of the patient's predicted response to that immunotherapy. Immunotherapy Portion 174 provides such information for anti-PD1 therapy, a therapeutic cancer vaccine, IFN ⁇ therapy, IL2 therapy, anti-CTLA4 therapy, and anti-angiogenic therapy. Patient specific information shown in Immunotherapy Portion 174 includes the patient's biomarker information relating to various immunotherapies and the patient's therapy scores calculated from their biomarkers.
- Efficacy Predictor Portion 176 a provides information indicative of the patient's predicted response to anti-PD1 therapy based on patient specific information presented in Immunotherapy Portion 174 .
- Efficacy Predictor Portion 176 b provides information indicative of the patient's predicted response to anti-CTLA4 therapy based on patient specific information presented in Immunotherapy Portion 174 .
- Targeted Therapy Selection Portion 178 provides patient specific information associated with a targeted therapy and information indicative of the patient's predicted response to the targeted therapy. Targeted Therapy Selection Portion 178 provides such information for sunitinib (SU), imatinib (IM), vemurafenib (VER), dabrafenib (DAB), trametinib, and pazopanib. Patient specific information shown in Targeted Therapy Selection Portion 178 includes a patient's biomarker information relating to various targeted therapies and the patient's therapy scores calculated from their biomarkers.
- the computer system 1500 may include one or more computer hardware processors 1510 and one or more articles of manufacture that comprise non-transitory computer-readable storage media (e.g., memory 1520 and one or more non-volatile storage devices 1530 ).
- the processor(s) 1510 may control writing data to and reading data from the memory 1520 and the non-volatile storage device(s) 1530 in any suitable manner.
- the processor(s) 1510 may execute one or more processor-executable instructions stored in one or more non-transitory computer-readable storage media (e.g., the memory 1520 ), which may serve as non-transitory computer-readable storage media storing processor-executable instructions for execution by the processor(s) 1510 .
- non-transitory computer-readable storage media e.g., the memory 1520
- FIG. 2 A is a flowchart of an illustrative computer-implemented process 200 for determining therapy scores for multiple therapies based on normalized biomarker scores, in accordance with some embodiments of the technology described herein.
- a therapy score provided herein may be indicative of a patient's response to a particular therapy based on the patient's normalized biomarker scores for biomarkers associated with the particular therapy.
- Process 200 may be performed by any suitable computing device(s). For example, process 200 may be performed by a laptop computer, a desktop computer, one or more servers, in a cloud computing environment, or in any other suitable way.
- Process 200 begins at act 202 , where sequencing data for a subject is obtained. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. In some embodiments, obtaining sequencing data comprises obtaining sequencing data from a biological sample obtained from the subject and/or from a database storing such information. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis” and “Obtaining Biomarker Information”.
- process 200 proceeds to act 204 , where biomarker information indicating distribution of values for biomarkers associated with multiple therapies is accessed.
- biomarker information indicating distribution of values for biomarkers associated with multiple therapies.
- information indicating a respective distribution of values (in a reference population) for each one of one or more biomarkers associated with the particular therapy may be accessed.
- biomarker information may be obtained from one or more databases, in some embodiments.
- process 200 proceeds to act 206 , where normalized biomarker scores for the subject are determined using sequencing data obtained at act 202 and the biomarker information obtained at act 204 .
- Normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising any number of biomarkers from any number of reference subjects. In that way, the subject's biomarker score is adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”.
- process 200 proceeds to act 208 , where therapy scores for each particular one of the multiple therapies are determined based on normalized biomarker scores for the biomarkers associated with the each particular one therapy.
- a therapy score may be calculated using multiple normalized biomarker scores as a sum, as a weighted sum, using a linear or generalized linear model, using a statistical model, or combinations thereof.
- the therapy score may be calculated using any suitable number of normalized biomarker scores, e.g., 2, 10, 50, or 100 normalized biomarker scores. Further aspects relating to determining therapy scores are provided in section “Predicting Therapy Response”.
- Therapy scores for any number of therapies may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way.
- GUI graphical user interface
- therapy scores and other patient related information may be provided to a user in a GUI as shown in FIGS. 9 - 14 .
- Systems and methods described herein may be used to assess the effectiveness of a therapy over time. Such systems and methods involve determining an impact score for a candidate therapy indicative of an impact of the candidate therapy on the patient based on the patient's biomarker information obtained prior to and subsequent to administration of the candidate therapy.
- FIG. 2 B is a flowchart of an illustrative computer-implemented process 220 for determining an impact score for a candidate therapy using first and second normalized biomarker scores, in accordance with some embodiments of the technology described herein.
- An impact score provided herein is indicative of a patient's response to a candidate therapy over time based on the patient's normalized biomarker scores obtained before, during and/or after treatment.
- a first normalized biomarker score may be obtained before treatment and a second normalized biomarker score may be obtained during and/or after treatment.
- Sequencing data for a subject prior to administration of a candidate therapy includes any sequencing data obtained for that subject any amount of time prior to treatment. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. Sequencing data for the subject may be obtained minutes, days, months, or years prior to treatment. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”.
- process 220 proceeds to act 224 , where second sequencing data for a subject subsequent to administration of a candidate therapy is obtained.
- Sequencing data for a subject subsequent to treatment includes any sequencing data obtained for that subject any amount of time subsequent to treatment. Sequencing data for the subject may be obtained minutes, days, months, or years subsequent to treatment. The second sequencing data may be a different type of sequencing data than the first sequencing data obtained prior to treatment. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”.
- biomarker information indicating a distribution of values for each of multiple biomarkers associated with the candidate therapy is accessed.
- Accessing biomarker information includes obtaining biomarker information associated with the candidate therapy from a variety of sources including from one or more databases.
- Biomarker information associated with the candidate therapy may be obtained from a subject prior to administration of a therapy and/or after administration of a therapy.
- first and second normalized biomarker scores for the subject are determined using first and second sequencing data and biomarker information.
- First and second normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising sets of biomarker values for the same biomarkers in multiple reference subjects. In that way, the subject's first and second biomarker score is adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”.
- process 220 proceeds to act 230 , where an impact score for the candidate therapy is determined based on first and second normalized biomarker scores.
- Such impact scores may be indicative of efficacy of the candidate therapy.
- impact scores may be used to select an additional therapy, stop administration of an ongoing therapy, and/or adjust how an ongoing therapy is being administered for the patient. Further aspects relating to determining impact scores are provided in section “Impact Scores”.
- Impact scores for any number and/or any type of candidate therapies may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way.
- GUI graphical user interface
- impact scores and other patient related information may be provided to a user in a GUI as shown in FIGS. 9 - 14 .
- Systems and methods described herein provide a multiple biomarker analysis that provides a more accurate prediction of a patient's response to therapy than that provided by a single biomarker analysis.
- FIG. 2 C is a flowchart of an illustrative computer-implemented process 240 for determining therapy scores for at least two selected therapies based on respective normalized biomarker scores for at least three biomarkers, in accordance with some embodiments of the technology described herein.
- Therapy scores may be determined for selected therapies of any suitable type.
- therapy scores may be determined for an immune checkpoint blockade therapy (e.g., anti-PD1 therapy) and a kinase inhibitor therapy (e.g., Sunitinib).
- therapy scores may be determined for two different immune checkpoint blockade therapies (e.g., anti-PD1 therapy and anti-CTLA4 therapy).
- Therapy scores may also be determined using any type of three biomarkers.
- therapy scores may be determined from at least three different genetic biomarkers or therapy scores may be determined from a genetic biomarker, a cellular biomarker, and an expression biomarker.
- Process 240 begins at act 242 , where sequencing data for a subject is obtained. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. In some embodiments, obtaining sequencing data comprises obtaining sequencing data from a biological sample obtained from the subject and/or from a database storing such information. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”.
- process 240 proceeds to act 244 , where biomarker information indicating distribution of values for the at least three biomarkers associated with the at least two therapies is accessed.
- biomarker information indicating distribution of values for the at least three biomarkers associated with the at least two therapies is accessed.
- information indicating a distribution of values for each of at least three biomarkers associated with each particular therapy may be accessed.
- at least six distributions of values may be accessed (e.g., at least three biomarker value distributions for three biomarkers associated with a first selected therapy and at least three biomarker value distributions for three biomarkers associated with a second selected therapy).
- Accessing biomarker information may include obtaining biomarker information from a variety of sources including one or more databases.
- process 240 proceeds to act 246 , where first and second sets of normalized biomarker scores for the subject are determined using the sequencing data obtained at act 242 and biomarker information obtained at act 244 .
- First and second sets of normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising sets of biomarker values for the same biomarkers in multiple reference subjects. In that way, the subject's first and second sets of biomarker scores are adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers.
- the first and second sets of normalized biomarkers may differ from each other, for example, in number of biomarkers and/or types of biomarkers.
- the first set of normalized biomarker scores may be associated with a first therapy and the second set of normalized biomarker scores may be associated with a second therapy. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”.
- process 240 proceeds to act 248 , where therapy scores for the at least two therapies are determined based on at least three normalized biomarker scores for each therapy.
- a therapy score may be calculated using the at least three normalized biomarker scores as a sum, as a weighted sum, using a linear or generalized linear model, using a statistical model, or combinations thereof.
- the therapy score may be calculated using any suitable number of normalized biomarker scores, e.g., 2, 10, 50, or 100 normalized biomarker scores. Further aspects relating to determining therapy scores are provided in section “Predicting Therapy Response”.
- Therapy scores for the at least two therapies and/or biomarker information used for determining therapy scores may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way.
- GUI graphical user interface
- therapy scores and other patient related information may be provided to a user in a GUI as shown in FIGS. 9 - 14 .
- Systems and methods described herein provide for determining more than one therapy score for a particular therapy. For example, a first and a second therapy score may be determined for a first therapy, and a first and second therapy score may be determined for a second therapy.
- FIG. 2 D is a flowchart of an illustrative computer-implemented process 260 for determining first and second therapy scores for a first and second therapy, respectively, based on normalized biomarker scores, in accordance with some embodiments of the technology described herein.
- First and second therapy scores may be determined using different biomarkers or different combinations of biomarkers. For example, a first therapy score is determined based on a patient's genetic biomarkers and a second therapy score is based on the patient's expression biomarkers. In another example, a first therapy score is determined based on a patient's genetic biomarkers and a second therapy score is based on the patient's genetic biomarkers and expression biomarkers.
- First and second therapy scores may be determined for different therapies and/or different types of therapies.
- first and second therapy scores may be determined for an immune checkpoint blockade therapy (e.g., anti-PD1 therapy) and a kinase inhibitor therapy (e.g., Sunitinib), respectively.
- first and second therapy scores may be determined for two different immune checkpoint blockade therapies (e.g., anti-PD1 therapy and anti-CTLA4 therapy).
- Process 260 begins at act 262 , where sequencing data for a subject is obtained. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. In some embodiments, obtaining sequencing data comprises obtaining sequencing data from a biological sample obtained from the subject and/or from a database storing such information. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”.
- biomarker information indicating distribution of values for biomarkers associated with at least two therapies.
- information indicating a distribution of values is obtained for each of one or more biomarkers associated with a first therapy
- information indicating a distribution of values is obtained for each of one or more biomarkers associated with a second therapy different from the first therapy.
- Accessing biomarker information may include obtaining biomarker information from a variety of sources including, for example, one or more databases
- process 260 proceeds to act 266 , where first and second sets of normalized biomarker scores for the subject are determined using sequencing data obtained at act 262 and biomarker information obtained at act 264 .
- First and second sets of normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising sets of biomarker values for the same biomarkers in multiple reference subjects. In that way, the subject's first and second sets of biomarker scores are adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers.
- the first and second sets of normalized biomarkers may differ from each other, for example, in number of biomarkers and/or types of biomarkers. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”.
- first and second therapy scores for the first and second therapies are determined based on normalized biomarker scores for each therapy.
- a therapy score may be calculated using the normalized biomarker scores as a sum, as a weighted sum, using a linear or generalized linear model, using a statistical model, or combinations thereof.
- the therapy score may be calculated using any suitable number of normalized biomarker scores, e.g., 2, 10, 50, or 100 normalized biomarker scores. Further aspects relating to determining therapy scores are provided in section “Predicting Therapy Response”.
- First and second therapy scores for first and second therapies and/or biomarker information used for determining therapy scores may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way.
- GUI graphical user interface
- therapy scores and other patient related information may be provided to a user in a GUI as shown in FIGS. 9 - 14 .
- Systems and methods described herein may be used to select patients for a clinical trial for a particular therapy based on the patient's predicted response to that therapy determined using the patient's biomarkers as described herein.
- the systems and methods described herein may be used to identify a patient as a member of a cohort for participation in a clinical trial.
- FIG. 2 E is a flowchart of an illustrative computer-implemented process 280 for identifying a subject as a member of a cohort using normalized biomarker scores, in accordance with some embodiments of the technology described herein.
- a subject may be identified as a member of a cohort for a clinical trial of any type of therapy, for example, a chemotherapy, an immunotherapy, an antibody therapy, and/or any combination thereof.
- the patient may be identified as a member of a cohort that will be administered the treatment or as a member of a cohort that will be administered a placebo.
- the patient may be not be identified as a member of a cohort, and thus may be excluded from participation in a clinical trial.
- Patients may be excluded from a clinical trial, in some embodiments, if those patients have been predicted to have an adverse reaction to a therapy determined using the patient's biomarkers as described herein and/or the patient's gene expression data as described in International patent application number PCT/US18/37018, entitled “Systems and Methods for Identifying Responders and Non-Responders to Immune Checkpoint Blockade Therapy,” filed Jun. 12, 2018, the entire contents of which are incorporated herein by reference.
- Process 280 begins at act 282 , where sequencing data for a subject is obtained. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. In some embodiments, obtaining sequencing data comprises obtaining sequencing data from a biological sample obtained from the subject and/or from a database storing such information. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”.
- biomarker information indicating a distribution of values for each of one or more biomarkers associated with a therapy is accessed.
- Accessing biomarker information may include obtaining biomarker information from a variety of sources, for example, one or more databases.
- process 280 proceeds to act 286 , where normalized biomarker scores for the subject are determined using sequencing data and biomarker information. Normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising sets of biomarker values for the same biomarkers in multiple reference subjects. In that way, the subject's biomarker score is adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”.
- process 280 proceeds to act 288 , where a subject is identified as a member of a cohort for participating in a clinical trial using biomarker scores.
- An identified subject in some embodiments, may be a subject that is likely to respond positively to the therapy being administered in the clinical trial.
- Such information may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way.
- GUI graphical user interface
- a patient can be identified and selected for participation in a clinical trial based on the patient's biomarker scores.
- Patients can also be identified for exclusion from the clinical trial, for example, patients predicted not likely to respond positively to the therapy and/or patients predicted to have an adverse reaction to the therapy.
- a software program may provide a user with a visual representation presenting information related to a patient's biomarker values (e.g., a biomarker score, and/or a therapy score, and/or an impact score), and predicted efficacy or determined efficacy of one or more therapies using a graphical user interface (GUI).
- a biomarker score e.g., a biomarker score, and/or a therapy score, and/or an impact score
- GUI graphical user interface
- the interactive GUI may provide the user of the software program with a visual representation of a patient's biomarker values and/or additional information related to the biomarker.
- FIGS. 6 A- 6 C are screenshots presenting such information to a user of the software program.
- FIG. 6 A is a screenshot presenting a patient's biomarker information associated with different immunotherapies that may be used to treat the patient.
- Shading reflects normalized biomarker value in terms of gradient from ⁇ 1 to 1. Shading intensity increasing as the biomarker value is increased. Shading with lines is assigned to positive biomarker values to distinguish them from negative biomarker values. Numeric “weight” of a biomarker is reflected in the width of the block with larger block width indicating a higher numeric weight.
- biomarkers with positive scores were calculated for anti-PD1 therapy indicating a predicted positive therapeutic effect of anti-PD1 therapy for a patient.
- biomarkers with negative scores were calculated for anti-VEGF therapy indicating a predicted negative therapeutic effect of anti-VEGF therapy for a patient.
- Numbers of positive biomarkers and negative biomarkers for a particular therapy may be similar for a patient. In such a case, the therapeutic effects of that therapy for the patient may not be predicted (i.e., may not be accurately predicted). Medium biomarker values for a particular therapy may also indicate that the therapeutic effects of that therapy for the patient may not be predicted (i.e., may not be accurately predicted).
- FIG. 6 B is a visual representation illustrating therapy scores calculated using normalized biomarker values shown in FIG. 6 A . Negative therapy scores are shown on the left side of the y-axis, and positive therapy scores are shown on the right side of the y-axis. Positive therapy scores are also differentiated from negative therapy scores by shading with lines.
- FIG. 6 C is a screenshot presenting information related to each biomarker and patient specific information related to that biomarker.
- Information presented includes, from left to right, a block representing each biomarker, a description of the biomarker, a graph showing the distribution of biomarker values, and a general description of the biomarker value as “high,” “low,” or “neutral”.
- the arrow in the graph indicates the patient's biomarker value.
- a normalized biomarker score may be labeled as a high score when the normalized biomarker score is in the top threshold percent (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%) of a distribution of values.
- a normalized biomarker score may be labeled as a low score when the normalized biomarker score is in the bottom threshold percent (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%) of a distribution of values.
- a normalized biomarker score may be considered neutral if it is not in the top threshold or the bottom threshold of a distribution of values.
- FIG. 9 is a graphic illustrating different types of screens that may be shown to a user of the software program. Each of the different screens illustrated in FIG. 9 may be used to present different types of information to the user.
- a screenshot of a control screen of the software program is shown in the middle of FIG. 9 .
- the control screen includes portions for presenting information relating to treatment selection, tumor properties, and clinical evidence of treatment efficacy and is described further with respect to FIGS. 10 - 15 .
- a user may interact with the control screen to obtain additional information about, for example, immunotherapy selection, targeted therapy selection, combination therapy design, tumor properties and tumor microenvironment, clinical evidence of targeted therapy efficacy, and clinical evidence of immunotherapy efficacy.
- the user may select a portion of the control screen (e.g., the immunotherapy portion) to view one or more additional screens presenting information relating to the selected portion. As shown in FIG. 9 , arrows point from a portion of the control screen that may be selected toward the screens presenting additional information related to the selected portion.
- the user may select the immunotherapy selection portion of the control screen to view one or more screens presenting information relating to various immunotherapies, biomarkers associated with an immunotherapy (e.g., genetic biomarkers, cellular biomarkers, and expression biomarkers), immune cell properties of the patient's tumor, and clinical trials (e.g., information from and/or regarding published clinical trials and ongoing clinical trials).
- biomarkers associated with an immunotherapy e.g., genetic biomarkers, cellular biomarkers, and expression biomarkers
- immune cell properties of the patient's tumor e.g., information from and/or regarding published clinical trials and ongoing clinical trials.
- the user may select the targeted therapy selection portion of the control screen to view one or more screens presenting information relating to various targeted therapies, biomarkers associated with targeted therapies (e.g., genetic biomarkers, cellular biomarkers, and/or expression biomarkers), properties of the patient's tumor associated with the targeted therapy, and clinical trials (e.g., published clinical trials and ongoing clinical trials).
- biomarkers associated with targeted therapies e.g., genetic biomarkers, cellular biomarkers, and/or expression biomarkers
- properties of the patient's tumor associated with the targeted therapy e.g., published clinical trials and ongoing clinical trials.
- the user may select the molecular-functional portrait (MF profile) portion of the control screen to view one or more screens presenting information relating to the patient's tumor microenvironment.
- information may include information about tumor properties (e.g., proliferation rate), angiogenesis, metastasis, cellular composition, cancer associated fibroblasts, pro-tumor immune environment, and anti-tumor immune environment.
- the user may select the clinical evidence of treatment efficacy portion of the control screen to view one or more screens presenting information relating to a therapy (e.g., an immunotherapy or targeted therapy).
- a therapy e.g., an immunotherapy or targeted therapy.
- information may include description of the therapy, therapy efficacy, potential adverse effects, related publications, treatment regimen, and patient survival data.
- the user may select a portion of the control screen to view one or more screens associated with an impact score for one or more candidate therapies, wherein the impact score is indicative of response of the subject to administration of the one or more candidate therapies.
- a user of the software program may interact with the GUI to log into the software program.
- the user may select a stored report to view a screen presenting information relating to the selected report.
- the user may select the create new report portion to view a screen for creating a new report.
- FIG. 10 is a screenshot presenting the selected patient's report including information related to the patient's sequencing data, the patient, and the patient's cancer.
- the therapy biomarkers portion presents information related to available therapies (e.g., immunotherapies and targeted therapies) and their predicted efficacy in the selected patient. Additional predictions of the efficacy of a therapy in the patient are provided in the machine predictor portion and additional portion (as shown in the left panel).
- the MF profile portion presents information relating to the molecular characteristics of a tumor including tumor genetics, pro-tumor microenvironment factors, and anti-tumor immune response factors (as shown in the middle panel).
- the clinical trials portion provides information relating to clinical trials (as shown in the right panel).
- the monotherapy or combinational therapy portion may be selected by the user to interactively design a personalized treatment for a patient.
- a user may select various portions of the screen to view additional information. For example, a user may select anti-PD1 in the immunotherapy biomarkers portion of the screen (as shown in the left panel) to view information relating to anti-PD1 treatment including biomarkers associated with anti-PD1 and tumor cell processes associated with anti-PD1 treatment.
- FIG. 11 is a screenshot presenting information related to anti-PD1 immunotherapy provided in response to selecting anti-PD1 immunotherapy (as shown by highlighting) in the immunotherapy biomarkers portion of the screen (as shown in the left panel).
- Information relating to biomarkers associated with anti-PD1 immunotherapy is provided in the biomarkers portion (as shown in the right panel).
- the biomarkers portion presents genetic biomarkers, cellular biomarkers, and expression biomarkers, as well as patient specific information related to those biomarkers.
- the user may select any one of the biomarkers presented in the biomarkers markers portion to view additional information relating to that biomarker including general information about the selected biomarker, patient specific information relating to the selected biomarker, information relating to tumor molecular processes associated with the selected biomarker, and treatment related information associated with the selected biomarker.
- the selected biomarker may be visually highlighted.
- a “visually highlighted” element may be highlighted through a difference in font (e.g., by italicizing, holding, and/or underlining), by surrounding the section with a visual object (e.g., a box), by “popping” the element out (e.g., by increasing the zoom for that element), by changing the color of an element, by shading the element, by incorporation of movement into the element (e.g., by causing the element to move), any combination of the foregoing in a portion or the whole of the element, or in any other suitable way.
- FIG. 12 is a screenshot presenting the mutational burden biomarker (as shown by highlighting) was selected by the user.
- the user may select another portion of the mutational burden biomarker to view a screen presenting information relating to the mutational burden biomarker such as relevant publications.
- FIG. 13 is a screenshot presenting information relating to the mutational burden biomarker (as shown in the middle panel) provided in response to the user selecting the mutational burden biomarker.
- the information may include a description of the biomarker, how the biomarker was calculated, the patient's particular biomarker value compared to other patients (as shown in a histogram), and information from publications relating to the selected biomarker.
- the system allows a user to interactively view biomarker information as it relates to a predicted response to a therapy.
- Clinical evidence of treatment efficacy for a therapy e.g., an immunotherapy or a targeted therapy
- a therapy e.g., an immunotherapy or a targeted therapy
- FIG. 14 is a screenshot presenting clinical trial data relating to anti-PD1 therapy effectivity in patients having stage IV metastatic melanoma (as shown in the right panel) provided in response to the user selecting anti-PD1 immunotherapy (as shown in the left panel).
- an effective amount of anti-cancer therapy described herein may be administered or recommended for administration to a subject (e.g., a human) in need of the treatment via a suitable route (e.g., intravenous administration).
- a suitable route e.g., intravenous administration
- the subject to be treated by the methods described herein may be a human patient having, suspected of having, or at risk for a cancer.
- a cancer include, but are not limited to, melanoma, lung cancer, brain cancer, breast cancer, colorectal cancer, pancreatic cancer, liver cancer, prostate cancer, skin cancer, kidney cancer, bladder cancer, or prostate cancer.
- the subject to be treated by the methods described herein may be a mammal (e.g., may be a human). Mammals may include, but are not limited to: farm animals (e.g., livestock), sport animals, laboratory animals, pets, primates, horses, dogs, cats, mice, and rats.
- a subject having a cancer may be identified by routine medical examination, e.g., laboratory tests, biopsy, PET scans, CT scans, or ultrasounds.
- a subject suspected of having a cancer might show one or more symptoms of the disorder, e.g., unexplained weight loss, fever, fatigue, cough, pain, skin changes, unusual bleeding or discharge, and/or thickening or lumps in parts of the body.
- a subject at risk for a cancer may be a subject having one or more of the risk factors for that disorder.
- risk factors associated with cancer include, but are not limited to, (a) viral infection (e.g., herpes virus infection), (b) age, (c) family history, (d) heavy alcohol consumption, (e) obesity, and (f) tobacco use.
- an anti-cancer therapeutic agent is an antibody, an immunotherapy, a molecular targeted therapy, a radiation therapy, a surgical therapy, and/or a chemotherapy.
- antibody anti-cancer agents include, but are not limited to, alemtuzumab (Campath), trastuzumab (Herceptin), Ibritumomab tiuxetan (Zevalin), Brentuximab vedotin (Adcetris), Ado-trastuzumab emtansine (Kadcyla), blinatumomab (Blincyto), Bevacizumab (Avastin), Cetuximab (Erbitux), ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), and panitumumab (Vectibix).
- an immunotherapy examples include, but are not limited to, a PD-1 inhibitor or a PD-L1 inhibitor, a CTLA-4 inhibitor, adoptive cell transfer, therapeutic cancer vaccines, oncolytic virus therapy, T-cell therapy, and immune checkpoint inhibitors.
- Examples of a molecular targeted therapy include, but are not limited to: Uprosertib, Alectinib, Crizotinib, Alisertib, Barasertib, Gilteritinib, Navitoclax, Bosutinib, Dasatinib, Nilotinib, Ponatinib, Imatinib, Dabrafenib, Vemurafenib, Encorafenib, Acalabrutinib, Ibrutinib, Verapamil, Tacrolimus, Abemaciclib, Ribociclib, Palbociclib, Celecoxib, Apricoxib, Selinexor, Plerixafor, Pinometostat, Rociletinib, Pyrotinib, Erlotinib, Gefitinib, Afatinib, Osimertinib, Varlitinib, Icotinib, Lapatinib, Neratinib, Tazemet
- radiation therapy examples include, but are not limited to, ionizing radiation, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes, and radiosensitizers.
- Examples of a surgical therapy include, but are not limited to, a curative surgery (e.g., tumor removal surgery), a preventive surgery, a laparoscopic surgery, and a laser surgery.
- a curative surgery e.g., tumor removal surgery
- a preventive surgery e.g., a laparoscopic surgery
- a laser surgery e.g., a laser surgery.
- chemotherapeutic agents include, but are not limited to, Carboplatin or Cisplatin, Docetaxel, Gemcitabine, Nab-Paclitaxel, Paclitaxel, Pemetrexed, and Vinorelbine.
- chemotherapy include, but are not limited to, Platinating agents, such as Carboplatin, Oxaliplatin, Cisplatin, Nedaplatin, Satraplatin, Lobaplatin, Triplatin, Tetranitrate, Picoplatin, Prolindac, Aroplatin and other derivatives; Topoisomerase I inhibitors, such as Camptothecin, Topotecan, irinotecan/SN38, rubitecan, Belotecan, and other derivatives; Topoisomerase H inhibitors, such as Etoposide (VP-16), Daunorubicin, a doxorubicin agent (e.g., doxorubicin, doxorubicin hydrochloride, doxorubicin analogs, or doxorubicin and salts or analogs thereof in liposomes), Mitoxantrone, Aclarubicin, Epirubicin, Idarubicin, Amrubicin, Amsacrine, Pirarubicin, Valrubicin
- an effective amount refers to the amount of each active agent required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents. Effective amounts vary, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient or clinician may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons, or for virtually any other reason(s).
- Empirical considerations such as the half-life of a therapeutic compound, generally contribute to the determination of the dosage.
- antibodies that are compatible with the human immune system such as humanized antibodies or fully human antibodies, may be used to prolong half-life of the antibody and to prevent the antibody being attacked by the host's immune system.
- Frequency of administration may be determined and adjusted over the course of therapy, and is generally (but not necessarily) based on treatment, and/or suppression, and/or amelioration, and/or delay of a cancer.
- sustained continuous release formulations of an anti-cancer therapeutic agent may be appropriate.
- Various formulations and devices for achieving sustained release are known in the art.
- dosages for an anti-cancer therapeutic agent as described herein may be determined empirically in individuals who have been administered one or more doses of the anti-cancer therapeutic agent. Individuals may be administered incremental dosages of the anti-cancer therapeutic agent. To assess efficacy of an administered anti-cancer therapeutic agent, one or more aspects of a cancer (e.g., tumor formation or tumor growth) may be analyzed.
- a cancer e.g., tumor formation or tumor growth
- an initial candidate dosage may be about 2 mg/kg.
- a typical daily dosage might range from about any of 0.1 ⁇ g/kg to 3 ⁇ g/kg to 30 ⁇ g/kg to 300 ⁇ g/kg to 3 mg/kg, to 30 mg/kg to 100 mg/kg or more, depending on the factors mentioned above.
- the treatment is sustained until a desired suppression or amelioration of symptoms occurs or until sufficient therapeutic levels are achieved to alleviate a cancer, or one or more symptoms thereof.
- An exemplary dosing regimen comprises administering an initial dose of about 2 mg/kg, followed by a weekly maintenance dose of about 1 mg/kg of the antibody, or followed by a maintenance dose of about 1 mg/kg every other week.
- other dosage regimens may be useful, depending on the pattern of pharmacokinetic decay that the practitioner (e.g., a medical doctor) wishes to achieve. For example, dosing from one-four times a week is contemplated.
- dosing ranging from about 3 ⁇ g/mg to about 2 mg/kg (such as about 3 ⁇ g/mg, about 10 ⁇ g/mg, about 30 ⁇ g/mg, about 100 ⁇ g/mg, about 300 ⁇ g/mg, about 1 mg/kg, and about 2 mg/kg) may be used.
- dosing frequency is once every week, every 2 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, or every 10 weeks; or once every month, every 2 months, or every 3 months, or longer.
- the progress of this therapy may be monitored by conventional techniques and assays and/or by monitoring the progress of the disease or cancer as described herein.
- the dosing regimen (including the therapeutic used) may vary over time.
- the anti-cancer therapeutic agent When the anti-cancer therapeutic agent is not an antibody, it may be administered at the rate of about 0.1 to 300 mg/kg of the weight of the patient divided into one to three doses, or as disclosed herein. In some embodiments, for an adult patient of normal weight, doses ranging from about 0.3 to 5.00 mg/kg may be administered.
- the particular dosage regimen e.g., dose, timing, and/or repetition, will depend on the particular subject and that individual's medical history, as well as the properties of the individual agents (such as the half-life of the agent, and other considerations well known in the art).
- an anti-cancer therapeutic agent for the purpose of the present disclosure, the appropriate dosage of an anti-cancer therapeutic agent will depend on the specific anti-cancer therapeutic agent(s) (or compositions thereof) employed, the type and severity of cancer, whether the anti-cancer therapeutic agent is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the anti-cancer therapeutic agent, and the discretion of the attending physician.
- the clinician will administer an anti-cancer therapeutic agent, such as an antibody, until a dosage is reached that achieves the desired result.
- an anti-cancer therapeutic agent can be continuous or intermittent, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners.
- the administration of an anti-cancer therapeutic agent e.g., an anti-cancer antibody
- the term “treating” refers to the application or administration of a composition including one or more active agents to a subject, who has a cancer, a symptom of a cancer, or a predisposition toward a cancer, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the cancer or one or more symptoms of the cancer, or the predisposition toward a cancer.
- the methods and systems herein may comprise recommendation of a treatment rather than treatment itself. In some embodiments, no recommendation of a treatment will be made. In certain embodiments, one or more potential treatments may be “ranked” or compared according to their predicted efficacy and/or subject or patient outcome.
- one or more potential treatments will not be “ranked” or compared according to their predicted efficacy and/or subject or patient outcome.
- information about a therapy e.g., the therapy score
- a user e.g., a doctor or clinician.
- Alleviating a cancer includes delaying the development or progression of the disease, or reducing disease severity (e.g., by at least one parameter). Alleviating the disease does not necessarily require curative results.
- “delaying” the development of a disease means to defer, hinder, slow, retard, stabilize, and/or postpone progression of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individuals being treated.
- a method that “delays” or alleviates the development or progress of a disease, or delays the onset of one or more complications of the disease is a method that reduces probability of developing one or more symptoms of the disease in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a number of subjects sufficient to give a statistically significant result.
- “Development” or “progression” of a disease means initial manifestations and/or ensuing progression of the disease. Development of the disease can be detected and assessed using clinical techniques known in the art. Alternatively or in addition to the clinical techniques known in the art, development of the disease may be detectable and assessed based on biomarkers described herein. However, development also refers to progression that may be undetectable. For purpose of this disclosure, development or progression refers to the biological course of the symptoms. “Development” includes occurrence, recurrence, and onset. As used herein “onset” or “occurrence” of a cancer includes initial onset and/or recurrence.
- the anti-cancer therapeutic agent (e.g., an antibody) described herein is administered to a subject in need of the treatment at an amount sufficient to reduce cancer (e.g., tumor) growth by at least 10% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater). In some embodiments, the anti-cancer therapeutic agent (e.g., an antibody) described herein is administered to a subject in need of the treatment at an amount sufficient to reduce cancer cell number or tumor size by at least 10% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more).
- the anti-cancer therapeutic agent is administered in an amount effective in altering cancer type (e.g., from a more severe to a less severe type; or from a worse prognosis to a better prognosis).
- the anti-cancer therapeutic agent is administered in an amount effective in reducing tumor formation, size, or metastasis.
- an anti-cancer therapeutic agent may be administered to the subject via injectable depot routes of administration such as using 1-, 3-, or 6-month depot injectable or biodegradable materials and methods.
- Injectable compositions may contain various carriers such as vegetable oils, dimethylactamide, dimethyformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like).
- water soluble anti-cancer therapeutic agents can be administered by the drip method, whereby a pharmaceutical formulation containing the antibody and a physiologically acceptable excipients is infused.
- Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution, and/or other suitable excipients.
- Intramuscular preparations e.g., a sterile formulation of a suitable soluble salt form of the anti-cancer therapeutic agent, can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, and/or 5% glucose solution.
- a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, and/or 5% glucose solution.
- an anti-cancer therapeutic agent is administered via site-specific or targeted local delivery techniques.
- site-specific or targeted local delivery techniques include various implantable depot sources of the agent or local delivery catheters, such as infusion catheters, an indwelling catheter, or a needle catheter, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, site specific carriers, direct injection, or direct application. See, e.g., PCT Publication No. WO 00/53211 and U.S. Pat. No. 5,981,568, the contents of each of which are incorporated by reference herein for this purpose.
- Targeted delivery of therapeutic compositions containing an antisense polynucleotide, expression vector, or subgenomic polynucleotides can also be used.
- Receptor-mediated DNA delivery techniques are described in, for example, Findeis et al., Trends Biotechnol. (1993) 11:202; Chiou et al., Gene Therapeutics: Methods And Applications Of Direct Gene Transfer (J. A. Wolff, ed.) (1994); Wu et al., J. Biol. Chem. (1988) 263:621; Wu et al., J. Biol. Chem. (1994) 269:542; Zenke et al., Proc. Natl. Acad. Sci. USA (1990) 87:3655; Wu et al., J. Biol. Chem. (1991) 266:338. The contents of each of the foregoing are incorporated by reference herein for this purpose.
- compositions containing a polynucleotide may be administered in a range of about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol.
- concentration ranges of about 500 ng to about 50 mg, about 1 ⁇ g to about 2 mg, about 5 ⁇ g to about 500 ⁇ g, and about 20 ⁇ g to about 100 ⁇ g of DNA or more can also be used during a gene therapy protocol.
- Therapeutic polynucleotides and polypeptides can be delivered using gene delivery vehicles.
- the gene delivery vehicle can be of viral or non-viral origin (e.g., Jolly, Cancer Gene Therapy (1994) 1:51; Kimura, Human Gene Therapy (1994) 5:845; Connelly, Human Gene Therapy (1995) 1:185; and Kaplitt, Nature Genetics (1994) 6:148).
- the contents of each of the foregoing are incorporated by reference herein for this purpose.
- Expression of such coding sequences can be induced using endogenous mammalian or heterologous promoters and/or enhancers. Expression of the coding sequence can be either constitutive or regulated.
- Viral-based vectors for delivery of a desired polynucleotide and expression in a desired cell are well known in the art.
- Exemplary viral-based vehicles include, but are not limited to, recombinant retroviruses (see, e.g., PCT Publication Nos. WO 90/07936: WO 94/03622; WO 93/25698; WO 93/25234; WO 93/11230; WO 93/10218; WO 91/02805; U.S. Pat. Nos. 5,219,740 and 4,777,127; GB Patent No. 2,200,651; and EP Patent No.
- alphavirus-based vectors e.g., Sindbis virus vectors, Semliki forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCC VR-1246) and Venezuelan equine encephalitis virus (ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532)
- AAV adeno-associated virus
- Non-viral delivery vehicles and methods can also be employed, including, but not limited to, polycationic condensed DNA linked or unlinked to killed adenovirus alone (see, e.g., Curiel, Hum. Gene Ther. (1992) 3:147); ligand-linked DNA (see, e.g., Wu, J. Biol. Chem. (1989) 264:16985); eukaryotic cell delivery vehicles cells (see, e.g., U.S. Pat. No. 5,814,482; PCT Publication Nos. WO 95/07994: WO 96/17072; WO 95/30763; and WO 97/42338) and nucleic charge neutralization or fusion with cell membranes. Naked DNA can also be employed.
- Exemplary naked DNA introduction methods are described in PCT Publication No. WO 90/11092 and U.S. Pat. No. 5,580,859.
- Liposomes that can act as gene delivery vehicles are described in U.S. Pat. No. 5,422,120; PCT Publication Nos. WO 95/13796; WO 94/23697; WO 91/14445; and EP Patent No. 0524968. Additional approaches are described in Philip, Mol. Cell. Biol. (1994) 14:2411, and in Woffendin, Proc. Natl. Acad. Sci. (1994) 91:1581. The contents of each of the foregoing are incorporated by reference herein for this purpose.
- an expression vector can be used to direct expression of any of the protein-based anti-cancer therapeutic agents (e.g., an anti-cancer antibody).
- protein-based anti-cancer therapeutic agents e.g., an anti-cancer antibody
- peptide inhibitors that are capable of blocking (from partial to complete blocking) a cancer causing biological activity are known in the art.
- more than one anti-cancer therapeutic agent such as an antibody and a small molecule inhibitory compound
- the agents may be of the same type or different types from each other. At least one, at least two, at least three, at least four, or at least five different agents may be co-administered.
- anti-cancer agents for administration have complementary activities that do not adversely affect each other.
- Anti-cancer therapeutic agents may also be used in conjunction with other agents that serve to enhance and/or complement the effectiveness of the agents.
- Treatment efficacy can be predicted as described herein for a patient prior to a treatment. Alternatively or in addition to, treatment efficacy can be predicted and/or determined as described herein over the course of treatment (e.g., before, during, and after treatment). See, e.g., Example 4 and Example 5 below.
- combination therapy embraces administration of more than one treatment (e.g., an antibody and a small molecule or an antibody and radiotherapy) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the agents or therapies, in a substantially simultaneous manner.
- Sequential or substantially simultaneous administration of each agent or therapy can be affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular, subcutaneous routes, and direct absorption through mucous membrane tissues.
- the agents or therapies can be administered by the same route or by different routes.
- a first agent e.g., a small molecule
- a second agent e.g., an antibody
- the term “sequential” means, unless otherwise specified, characterized by a regular sequence or order, e.g., if a dosage regimen includes the administration of an antibody and a small molecule, a sequential dosage regimen could include administration of the antibody before, simultaneously, substantially simultaneously, or after administration of the small molecule, but both agents will be administered in a regular sequence or order.
- the term “separate” means, unless otherwise specified, to keep apart one from the other.
- the term “simultaneously” means, unless otherwise specified, happening or done at the same time, i.e., the agents of the disclosure are administered at the same time.
- substantially simultaneously means that the agents are administered within minutes of each other (e.g., within 10 minutes of each other) and intends to embrace joint administration as well as consecutive administration, but if the administration is consecutive it is separated in time for only a short period (e.g., the time it would take a medical practitioner to administer two agents separately).
- concurrent administration and substantially simultaneous administration are used interchangeably.
- Sequential administration refers to temporally separated administration of the agents or therapies described herein.
- Combination therapy can also embrace the administration of the anti-cancer therapeutic agent (e.g., an antibody) in further combination with other biologically active ingredients (e.g., a vitamin) and non-drug therapies (e.g., surgery or radiotherapy).
- the anti-cancer therapeutic agent e.g., an antibody
- other biologically active ingredients e.g., a vitamin
- non-drug therapies e.g., surgery or radiotherapy.
- any combination of anti-cancer therapeutic agents may be used in any sequence for treating a cancer.
- the combinations described herein may be selected on the basis of a number of factors, which include but are not limited to the effectiveness of altering a biomarker, reducing tumor formation or tumor growth, and/or alleviating at least one symptom associated with the cancer, or the effectiveness for mitigating the side effects of another agent of the combination.
- a combined therapy as provided herein may reduce any of the side effects associated with each individual members of the combination, for example, a side effect associated with an administered anti-cancer agent.
- Biomarkers used herein were obtained from published clinical studies shown in Table 1.
- biomarkers that split the patient cohorts treated with a particular therapy by a clinical measure e.g., overall survival (OS), progression-free survival (PFS), objective response rate (ORR), ect.
- OS overall survival
- PFS progression-free survival
- ORR objective response rate
- ect. objective response rate
- Biomarkers were defined as either positive biomarkers or negative biomarkers based on whether the parameter value of the biomarker corresponds to an increase or decrease in therapy response. Biomarkers were defined as positive biomarkers if their biomarker parameter value correlating to a positive therapy outcome was high. Biomarkers were defined as negative biomarkers if their biomarker parameter value correlating to a negative therapy outcome was high.
- Biomarkers with digital properties such as certain mutations (e.g., BRAFV600E), were normalized using a binary system, where presence of a biomarker corresponded to 1, and absence of a biomarker corresponded to 0.
- Biomarkers associated with protein expression such as those determined from tissue staining experiments, were assigned their corresponding gene expression (e.g., target protein assigned target mRNA expression level).
- Biomarkers associated with cellular composition in the tumor microenvironment were recalculated with bioinformatics cell deconvolution packages based on RNAseq data (e.g., MCPcounter, CIBERSORT).
- Normalized biomarker scores were calculated for a large patient cohort in which patients were diagnosed based on their tumor biopsy. Data was obtained from publicly available databases of human cancer biopsies, and data was normalized for a particular patient using one of the below formulas according to the distribution of biomarker values calculated for the large patient cohort.
- Normalized parameter values in terms of “high” and “low” were calculated based on the Z-score of the parameter value using predefined mathematical functions where the normalized parameter value ranges from ⁇ 1 to 1 depending on Z-score. Mean and standard deviation were taken from a previously calculated distribution of parameter values for the large patient cohort to which the patient belonged.
- the function was set so that a zero value of the parameter fell in the middle of the distribution, and the highest values were assigned to parameters at the extreme upper end of the distribution.
- C +cutoff normalized threshold value representing a “high” parameter value
- C ⁇ cutoff normalized threshold value representing a “low” parameter value
- Threshold value C +cutoff (C ⁇ cutoff ) was equal to 1 ( ⁇ 1), indicating that 15% of patients had a high biomarker value, and 15% of patients had a low biomarker value. Different cut-offs may be used depending on the biomarkers involved in the calculation.
- each biomarker was transformed to the same range scale. Thus, a value equal to 1 represents a “high” parameter value, and a value equal to ⁇ 1 represents a “low” parameter value.
- Parameter values equal or close to 0 reflect median parameter values according to the distribution.
- a graphical representation of biomarker value distribution for a large patient cohort is shown in FIG. 3 .
- Biomarkers were assigned weights indicative of their predictive significance based on whether the biomarker was obtained from a large or small patient cohort. Biomarkers obtained from studies using large patient cohorts may have higher predictive significance, and therefore these biomarkers were assigned an initial numeric weight of 3. Biomarkers obtained from studies using small patient cohorts may have lower predictive significance, and therefore these biomarkers were assigned an initial numeric weight of 1.
- Biomarkers were assigned weights indicative of their predictive significance based on the role of the biomarker with respect to a therapy. For example, when analyzing biomarkers for treatment with an anti-PD1 therapy, PDL expression was a significant biomarker that was assigned a higher numeric weight than a less significant biomarker such as gender.
- Biomarker significance in terms of “weight” was defined by expert assessment or clinical studies where the biomarker was identified. Significance or weight was based on clinical measures (e.g., patient outcome) that split two cohorts of patients divided by biomarker value. If the difference among clinical outcomes for a biomarker was large (p-value ⁇ 0.01), it was assigned a high weight. If the clinical difference for a biomarker was minimal (0.01 ⁇ p-value ⁇ 0.05), the biomarker weight was assigned a low weight.
- biomarker significance was calculated for a biomarker within a set of biomarkers using machine learning algorithms. This approach involved extensive “training” of datasets. A set of biomarkers obtained from literature was tested mathematically to improve weights manually assigned to biomarkers. The algorithm provided a list of significant biomarkers and insignificant biomarkers. Insignificant biomarkers were excluded from the initial set without loss of prediction accuracy.
- Patient 1 and Patient 2 had more positive biomarkers, and thus had higher therapy scores ( FIG. 4 ).
- Patient 4 had similar numbers of positive and negative biomarkers and Patient 5 had biomarkers with neutral values, and thus these patients had therapy scores of zero ( FIG. 4 ).
- Patient 3 had a greater number of negative biomarkers, and thus has a negative therapy score ( FIG. 4 ).
- Therapy scores for different therapies were calculated for a non-responsive patient (Patient 1) and a responsive patient (Patient 2) with respect to their response to the anti-PD1 therapy Pembrolizumab. Based on the calculated therapy scores, Patient 1 was likely non-responsive to other treatments including anti-CTLA4 therapy, IL-2 therapy, vaccine therapy, and Bevacizumab ( FIG. 5 ). However, Patient 1's therapy score predicted a likely response to IFN- ⁇ therapy ( FIG. 5 ). Patient 2's therapy scores predicted a likely response to each treatment. These results demonstrated that therapy scores predicted both a response and a non-response to a therapy.
- Treatment scores were calculated as described herein for an anti-PD1 therapy dataset and an anti-CTLA4 dataset. Patients treated with an anti-PD1 therapy having higher therapy scores calculated as a sum of positive and negative biomarkers were more likely to respond to therapy, and patients with negative therapy scores were unlikely to respond to therapy ( FIG. 7 A ). Similar results were obtained for patients treated with an anti-CTLA4 therapy ( FIG. 7 B ).
- Predictive accuracy was improved by using a prediction cut-off.
- analysis of the anti-PD1 therapy dataset showed that the prediction rate was 73% when the non-response cut-off was lower than zero and 88% when the non-response cut-off was lower than ⁇ 1 ( FIG. 7 C ).
- the prediction rate was 80% when the response cut-off was higher than zero and improved to 91% when the response cut-off was higher than 1 ( FIG. 7 C ).
- Therapy response rate predictions based on certain cut-offs for various therapies are shown in Table 3.
- Non-response Response cut-off Prediction cut-off Prediction Therapy (lower than) rate (higher than) rate aPDI therapy 0 73% 0 80% aCTLA4 therapy ⁇ 1 77% — — IFNa therapy 0 100% 0 70% MAGEA-3 vaccine ⁇ 2 94% 0 50% Bevacizumab ⁇ 1 80% 1 80% Rituximab Based — — 0 100%
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomark
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies
- a method comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies, each of the therapy scores indicative of predicted response of the subject to administration of a respective therapy in the plurality of therapies.
- the plurality of biomarkers includes a first biomarker, and determining a normalized score for each biomarker in at least the subject subset of the plurality of biomarkers comprises: determining a first normalized score for the first biomarker using the distribution of values for the first biomarker. In some embodiments, determining the first normalized score comprises: determining a first un-normalized score for the first biomarker using the sequencing data; determining a first Z-score based on the first distribution of values for the first biomarker; and determining the first normalized score for the first biomarker based on the first un-normalized score and the first Z-score.
- determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies as a sum of two or more scores in the set of normalized biomarker scores for the subject.
- determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies at least in part by: determining weights for two or more scores in the set of normalized biomarker scores for the subject; and determining the first therapy score as a weighted sum of the two or more scores, summands of the sum being weighted by the determined weights.
- determining the weights comprises determining the weights using a statistical model. In some embodiments, determining the weights comprises determining the weights using a generalized linear model. In some embodiments, determining the weights comprises determining the weights using a logistic regression model.
- the plurality of therapies comprises a first therapy and a second therapy different from the first therapy
- determining therapy scores for the plurality of therapies comprises: determining a first therapy score for the first therapy using a first subset of the set of normalized biomarker scores for the subject; and determining a second therapy score for the second therapy using a second subset of the set of normalized biomarker scores for the subject, wherein the second subset is different from the first subset.
- Some embodiments include providing the determined therapy scores to a user. Some embodiments include ranking the plurality of therapies based on the determined therapy scores. Some embodiments include recommending at least one of the plurality of therapies for the subject based on the determined therapy scores.
- recommending the at least one of the plurality of therapies comprises: ranking the plurality of therapies based on the determined therapy scores; and recommending at least a threshold number of top-ranked therapies for the subject.
- the plurality of therapies comprises at least two therapies selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
- the plurality of biomarkers associated with the anti-PD1 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- the plurality of biomarkers associated with the anti-CTLA4 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- the plurality of biomarkers associated with the IL-2 therapy comprises at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- the plurality of biomarkers associated with the IFN alpha therapy comprises at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- the plurality of biomarkers associated with the anti-cancer vaccine therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- the plurality of biomarkers associated with the anti-angiogenic therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- the plurality of biomarkers associated with the anti-CD20 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, the anti-CD20 therapy is rituximab.
- Some embodiments further include generating a graphical user interface (GUI) comprising: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- GUI graphical user interface
- the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element.
- the first therapy is associated with a first therapy score and the second therapy is associated with a second therapy score, and wherein the first portion and the second portion are positioned, relative to one another in the GUI, based on relative magnitude of the first therapy score and the second therapy score.
- each of the plurality of biomarkers is selected from the group consisting of: a genetic biomarker, a cellular biomarker, a saccharide biomarker, a lipid biomarker, a heterocyclic biomarker, an elementary compound biomarker, an imaging biomarker, an anthropological biomarker, a personal habit biomarker, a disease-state biomarker, and an expression biomarker.
- the one or more genetic biomarkers includes a gene or marker described in the description and/or the figures.
- one or more genetic biomarkers are selected from the group consisting of: interferons, cytotoxic proteins, enzymes, cell adhesion proteins, extracellular matrix proteins and polysaccharides, cell growth factors, cell differentiation factors, transcription factors, and intracellular signaling proteins.
- the one or more genetic biomarkers is selected from the group consisting of: a cytokine, a chemokine, a chemokine receptor, and an interleukin.
- the value of one or more cellular biomarkers is determined through analysis of the number of one or more types of cells or the percentage of one or more types of cells within the biological sample.
- the one or more types of cells are selected from the group consisting of malignant cancerous cells, leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- the value of one or more expression biomarkers is determined through analysis of the expression level or enzymatic activity of the nucleic acid or protein of the expression biomarker.
- the sequencing data is one or more of: DNA sequencing data, RNA sequencing data, or proteome sequencing data.
- the sequencing data is obtained using one or more of the following techniques: whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray, DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP) genotyping.
- WGS whole genome sequencing
- WES whole exome sequencing
- SNP single nucleotide polymorphism
- each of the at least one biological samples is a bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy.
- the tissue biopsy comprises one or more samples from one or more tumors or tissues known or suspected of having cancerous cells.
- the biomarker information also comprises results from one or more of the following types of analyses: blood analysis, cytometry analysis, histological analysis, immunohistological analysis, and patient history analysis.
- each of the therapies are selected from the group consisting of: surgery, radiation therapy, chemotherapy, immunotherapy, viral therapy, targeted therapy, hormone therapy, transplants, phototherapy, cryotherapy, and hyperthermia. In some embodiments, each of the therapies are selected from immunotherapy and targeted therapy.
- the therapy scores are indicative of response of the subject to administration of one therapy in the plurality of therapies. In some embodiments, the therapy scores are indicative of predicted response of the subject to administration of multiple therapies in the plurality of therapies.
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- a method comprising: using at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- determining the impact score for the candidate therapy further comprises: determining, using the first and second sets of normalized biomarker scores, a difference score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of biomarker difference scores for the subject; and determining, using the set of biomarker difference scores, the impact score for the candidate therapy.
- determining the impact score for the candidate therapy further comprises: determining, using the first and second sets of normalized biomarker scores, a first and second subject subset score for the subject subset of the plurality of biomarkers determining a subject subset difference score, wherein the subject subset difference score is determined using the first and second subject subset score; and determining, using the subject subset difference score, the impact score for the candidate therapy.
- the candidate therapy is selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
- the plurality of biomarkers associated with the anti-PD1 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- the plurality of biomarkers associated with the anti-CTLA4 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- the plurality of biomarkers associated with the IL-2 therapy comprises at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- the plurality of biomarkers associated with the IFN alpha therapy comprises at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- the plurality of biomarkers associated with the anti-cancer vaccine therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- the plurality of biomarkers associated with the anti-angiogenic therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- the plurality of biomarkers associated with the anti-CD20 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, wherein determining the biomarker difference scores for the subject comprises determining a difference score for at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, wherein determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, the anti-CD20 therapy is rituximab.
- Some embodiments include generating a graphical user interface (GUI) comprising a first portion associated with the candidate therapy, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a difference score of the respective biomarker; and displaying the generated GUI.
- GUI graphical user interface
- Some embodiments include generating a graphical user interface (GUI) comprising: a first portion associated with the candidate therapy, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a subject subset difference score; and displaying the generated GUI.
- the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element.
- Some embodiments include, in response to receiving, via the GUI, a user selection of the candidate therapy, presenting, via the GUI, information about at least one biomarker with which at least one of the first plurality of GUI elements is associated.
- determining the difference score for each biomarker in at least the subject subset comprises: determining a first normalized score for a first biomarker using the first sequencing data; determining a second normalized score for the first biomarker using the second sequencing data; and determining a first difference score based on a difference between the first and second normalized scores.
- determining the difference score for each biomarker in at least the subject subset comprises: determining a first subject subset score for at least three biomarkers using the first sequencing data; determining a second subject subset score for at least three biomarkers using the second sequencing data; and determining a first subject subset difference score based on a difference between the first and second subject subset scores.
- the biomarker information includes a first distribution of values for the first biomarker across a first group of people, and wherein determining the first normalized score comprises: determining a first un-normalized score for the first biomarker using the first sequencing data; determining a first Z-score based on the first distribution of values for the first biomarker; and determining the first normalized score for the first biomarker based on the first un-normalized score and the first Z-score.
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a
- a method comprising using the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized scores as input to the statistical model to obtain a second therapy
- the plurality of biomarkers includes a first biomarker
- determining a normalized score for each biomarker in at least the subject subset of the plurality of biomarkers comprises: determining a first normalized score for the first biomarker using the distribution of values for the first biomarker.
- determining the first normalized score comprises: determining an un-normalized score for the first biomarker using the sequencing data; determining a Z-score based on the first distribution of values for the first biomarker; and determining a normalized score for the first biomarker based on the un-normalized score and the Z-score.
- determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies as a sum of two or more scores in the set of normalized biomarker scores for the subject.
- determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies at least in part by: determining weights for two or more scores in the set of normalized biomarker scores for the subject; and determining the first therapy score as a sum of the two or more scores, summands of the sum being weighted by the determined weights.
- determining the weights comprises determining the weights using a machine learning technique.
- determining the weights comprises determining the weights using a generalized linear model.
- determining the weights comprises determining the weights using a logistic regression model.
- the plurality of therapies comprises a first therapy and a second therapy different from the first therapy
- determining therapy scores for the plurality of therapies comprises: determining a first therapy score for the first therapy using a first subset of the set of normalized biomarker scores for the subject; and determining a second therapy score for the second therapy using a second subset of the set of normalized biomarker scores for the subject, wherein the second subset is different from the first subset.
- Some embodiments include recommending at least one of the plurality of therapies for the subject based on the determined therapy scores. Some embodiments include ranking the plurality of therapies based on the determined therapy scores. In some embodiments, recommending the at least one of the plurality of therapies comprises: ranking the plurality of therapies based on the determined therapy scores; and recommending at least a threshold number of top-ranked therapies for the subject.
- the plurality of therapies comprise at least two therapies selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
- the plurality of biomarkers associated with the anti-PD1 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- the plurality of biomarkers associated with the anti-CTLA4 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- the plurality of biomarkers associated with the IL-2 therapy comprises at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- the plurality of biomarkers associated with the IFN alpha therapy comprises at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- the plurality of biomarkers associated with the anti-cancer vaccine therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- the plurality of biomarkers associated with the anti-angiogenic therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- the plurality of biomarkers associated with the anti-CD20 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, the anti-CD20 therapy is rituximab.
- the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element.
- the first therapy is associated with a first therapy score and the second therapy is associated with a second therapy score, and wherein the first portion and the second portion are positioned, relative to one another in the GUI, based on relative magnitude of the first therapy score and the second therapy score.
- each of the plurality of biomarkers is selected from the group consisting of: a genetic biomarker, a cellular biomarker, a saccharide biomarker, a lipid biomarker, a heterocyclic biomarker, an elementary compound biomarker, an imaging biomarker, an anthropological biomarker, a personal habit biomarker, a disease-state biomarker, and an expression biomarker.
- the value of one or more genetic biomarkers is determined through the identification of one or more mutations, insertions, deletions, rearrangements, fusions, copy number variations (CNV), or single nucleotide variants (SNV) in the nucleic acid or protein of the genetic biomarker.
- CNV copy number variations
- SNV single nucleotide variants
- the one or more genetic biomarkers includes a gene or marker described in the description and/or the figures.
- one or more genetic biomarkers are selected from the group consisting of: interferons, cytotoxic proteins, enzymes, cell adhesion proteins, extracellular matrix proteins and polysaccharides, cell growth factors, cell differentiation factors, transcription factors, and intracellular signaling proteins.
- the one or more genetic biomarkers is selected from the group consisting of: a cytokine, a chemokine, a chemokine receptor, and an interleukin.
- the value of one or more cellular biomarkers is determined through analysis of the number of one or more types of cells or the percentage of one or more types of cells within the biological sample.
- the one or more types of cells are selected from the group consisting of malignant cancerous cells, leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- malignant cancerous cells leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- MDSCs myeloid-derived suppressor cells
- the value of one or more expression biomarkers is determined through analysis of the expression level or enzymatic activity of the nucleic acid or protein of the expression biomarker.
- the sequencing data is one or more of: DNA sequencing data, RNA sequencing data, or proteome sequencing data.
- the sequencing data is obtained using one or more of the following techniques: whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray, DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP) genotyping.
- WGS whole genome sequencing
- WES whole exome sequencing
- SNP single nucleotide polymorphism
- each of the at least one biological samples is a bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy.
- the tissue biopsy comprises one or more samples from one or more tumors or tissues known or suspected of having cancerous cells.
- the biomarker information also comprises results from one or more of the following types of analyses: blood analysis, cytometry analysis, histological analysis, immunohistological analysis, and patient history analysis.
- each of the therapies are selected from the group consisting of: surgery, radiation therapy, chemotherapy, immunotherapy, viral therapy, targeted therapy, hormone therapy, transplants, phototherapy, cryotherapy, and hyperthermia.
- each of the therapies are selected from immunotherapy and targeted therapy.
- the therapy scores are indicative of response of the subject to administration of one therapy in the plurality of therapies. In some embodiments, the therapy scores are indicative of response of the subject to administration of multiple therapies in the plurality of therapies.
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input
- a method comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized biomarker scores
- the plurality of biomarkers includes a first biomarker
- determining a normalized score for each biomarker in at least the subject subset of the plurality of biomarkers comprises: determining a first normalized score for the first biomarker using the distribution of values for the first biomarker.
- determining the first normalized score comprises: determining an un-normalized score for the first biomarker using the sequencing data; determining a Z-score based on the first distribution of values for the first biomarker; and determining a normalized score for the first biomarker based on the un-normalized score and the Z-score.
- determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies as a sum of two or more scores in the set of normalized biomarker scores for the subject.
- determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies at least in part by: determining weights for two or more scores in the set of normalized biomarker scores for the subject; and determining the first therapy score as a sum of the two or more scores, summands of the sum being weighted by the determined weights.
- determining the weights comprises determining the weights using a machine learning technique. In some embodiments, determining the weights comprises determining the weights using a generalized linear model. In some embodiments, determining the weights comprises determining the weights using a logistic regression model.
- the plurality of therapies comprises a first therapy and a second therapy different from the first therapy
- determining therapy scores for the plurality of therapies comprises: determining a first therapy score for the first therapy using a first subset of the set of normalized biomarker scores for the subject; and determining a second therapy score for the second therapy using a second subset of the set of normalized biomarker scores for the subject, wherein the second subset is different from the first subset.
- Some embodiments include recommending at least one of the plurality of therapies for the subject based on the determined therapy scores.
- recommending the at least one of the plurality of therapies comprises: ranking the plurality of therapies based on the determined therapy scores; and recommending at least a threshold number of top-ranked therapies for the subject.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2.
- the anti-CD20 therapy is rituximab.
- Some embodiments include generating a graphical user interface (GUI) comprising: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- GUI graphical user interface
- the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element.
- Some embodiments include in response to receiving, via the GUI, a user selection of the first therapy, presenting, via the GUI, information about at least one biomarker with which at least one of the first plurality of GUI elements is associated.
- the first therapy is associated with a first therapy score and the second therapy is associated with a second therapy score, and wherein the first portion and the second portion are positioned, relative to one another in the GUI, based on relative magnitude of the first therapy score and the second therapy score.
- each of the plurality of biomarkers is selected from the group consisting of: a genetic biomarker, a cellular biomarker, a saccharide biomarker, a lipid biomarker, a heterocyclic biomarker, an elementary compound biomarker, an imaging biomarker, an anthropological biomarker, a personal habit biomarker, a disease-state biomarker, and an expression biomarker.
- the value of one or more genetic biomarkers is determined through the identification of one or more mutations, insertions, deletions, rearrangements, fusions, copy number variations (CNV), or single nucleotide variants (SNV) in the nucleic acid or protein of the genetic biomarker.
- the one or more genetic biomarkers includes a gene or marker described in the description and/or the figures.
- one or more genetic biomarkers are selected from the group consisting of: interferons, cytotoxic proteins, enzymes, cell adhesion proteins, extracellular matrix proteins and polysaccharides, cell growth factors, cell differentiation factors, transcription factors, and intracellular signaling proteins.
- the one or more genetic biomarkers is selected from the group consisting of: a cytokine, a chemokine, a chemokine receptor, and an interleukin.
- the value of one or more cellular biomarkers is determined through analysis of the number of one or more types of cells or the percentage of one or more types of cells within the biological sample.
- the one or more types of cells are selected from the group consisting of malignant cancerous cells, leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- the value of one or more expression biomarkers is determined through analysis of the expression level or enzymatic activity of the nucleic acid or protein of the expression biomarker.
- the sequencing data is one or more of: DNA sequencing data, RNA sequencing data, or proteome sequencing data.
- the sequencing data is obtained using one or more of the following techniques: whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray, DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP) genotyping.
- WGS whole genome sequencing
- WES whole exome sequencing
- SNP single nucleotide polymorphism
- each of the at least one biological samples is a bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy.
- the tissue biopsy comprises one or more samples from one or more tumors or tissues known or suspected of having cancerous cells.
- the biomarker information also comprises results from one or more of the following types of analyses: blood analysis, cytometry analysis, histological analysis, immunohistological analysis, and patient history analysis.
- each of the therapies are selected from the group consisting of: surgery, radiation therapy, chemotherapy, immunotherapy, viral therapy, targeted therapy, hormone therapy, transplants, phototherapy, cryotherapy, and hyperthermia. In some embodiments, each of the therapies are selected from immunotherapy and targeted therapy.
- the therapy scores are indicative of response of the subject to administration of one therapy in the plurality of therapies. In some embodiments, the therapy scores are indicative of response of the subject to administration of multiple therapies in the plurality of therapies.
- a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or
- At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one
- a method comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one or more cohorts in which the subject is a member.
- the at least one candidate therapy is associated with a clinical trial, optionally wherein the clinical trial is ongoing or the clinical trial is recruiting.
- the positive outcome is an improvement in one or more aspects of a cancer or in one or more cancer symptoms.
- the improvement in one or more aspects of a cancer or one or more cancer symptoms is selected from the group consisting of: decrease in tumor size, decrease in tumor number, decrease in number or percentage of cancerous cells in the body of the subject, and slowing of cancer growth.
- the negative outcome is a cancer therapy-related adverse effect, an deterioration in one or more aspects of a cancer, or a deterioration in one or more cancer symptoms.
- the cancer therapy-related adverse effect is selected from: cutaneous toxicity, thrombocytopenia, hepatotoxicity, neurotoxicity, nephrotoxicity, cardiotoxicity, hemorrhagic cystitis, immune-related toxicity, and death.
- the deterioration in one or more aspects of a cancer or one or more cancer symptoms is selected from the group consisting of: increase in tumor size, increase in tumor number, increase in number or percentage of cancerous cells in the body of the subject, no slowing of cancer growth, and death.
- the sequencing data is one or more of: DNA sequencing data, RNA sequencing data, or proteome sequencing data.
- the sequencing data is obtained using one or more of the following techniques: whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray, DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP) genotyping.
- WGS whole genome sequencing
- WES whole exome sequencing
- SNP single nucleotide polymorphism
- the biological sample is from a tumor or tissue known or suspected of having cancerous cells.
- each of the at least one biological samples is a bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy.
- the biological sample is blood.
- Some embodiments include generating a graphical user interface (GUI) comprising: a first portion associated with the at least one candidate therapy, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a difference score of the respective biomarker; and displaying the generated GUI.
- the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element.
- Some embodiments include in response to receiving, via the GUI, a user selection of the at least one candidate therapy, presenting, via the GUI, information about at least one biomarker with which at least one of the first plurality of GUI elements is associated.
- program or “software” are used herein in a generic sense to refer to any type of computer code or set of processor-executable instructions that can be employed to program a computer or other processor (physical or virtual) to implement various aspects of embodiments as discussed above. Additionally, according to one aspect, one or more computer programs that when executed perform methods of the technology described herein need not reside on a single computer or processor, but may be distributed in a modular fashion among different computers or processors to implement various aspects of the technology described herein.
- Processor-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices.
- program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types.
- functionality of the program modules may be combined or distributed.
- data structures may be stored in one or more non-transitory computer-readable storage media in any suitable form.
- data structures may be shown to have fields that are related through location in the data structure. Such relationships may likewise be achieved by assigning storage for the fields with locations in a non-transitory computer-readable medium that convey relationship between the fields.
- any suitable mechanism may be used to establish relationships among information in fields of a data structure, including through the use of pointers, tags or other mechanisms that establish relationships among data elements.
- inventive concepts may be embodied as one or more processes, of which examples have been provided.
- the acts performed as part of each process may be ordered in any suitable way.
- embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.
- the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
- This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified.
- “at least one of A and B” can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
- a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
- patient and “subject” may be used interchangeably. Such terms may include, but are not limited to, human subjects or patients. Such terms may also include non-human primates or other animals.
Abstract
Techniques for determining therapy scores for at least two of an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy. The techniques include determining, using sequencing data for the subject and information indicating distribution of biomarker values across one or more reference populations, a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; and providing the second set of normalized biomarker scores as input to the statistical model to obtain a second therapy score for the second therapy.
Description
- This application claims the benefit under 35 U.S.C. § 119(e) of the filing date of U.S. provisional patent application Ser. No. 62/518,787, entitled “Systems and Methods for Identifying Cancer Treatments from Sequence Data”, filed Jun. 13, 2017 and U.S. provisional patent application Ser. No. 62/598,440, entitled “Systems and Methods Identifying Cancer Treatments from Sequence Data,” filed Dec. 13, 2017, the entire contents of each of which are incorporated herein by reference.
- This application is filed on the same day as International Application No.: PCT/US18/37017, entitled “SYSTEMS AND METHODS FOR GENERATING, VISUALIZING AND CLASSIFYING MOLECULAR FUNCTIONAL PROFILES”, bearing Attorney Docket No. B1462.70002WO00; International Application No.: PCT/US18/37018, entitled “SYSTEMS AND METHODS FOR IDENTIFYING RESPONDERS AND NON-RESPONDERS TO IMMUNE CHECKPOINT BLOCKADE THERAPY”, bearing Attorney Docket No. B1462.70003WO00; and International Application No.: PCT/US18/37008, entitled “SYSTEMS AND METHODS FOR IDENTIFYING CANCER TREATMENTS FROM NORMALIZED BIOMARKER SCORES”, bearing Attorney Docket No. B1462.70004WO00, the entire contents of each of which are incorporated herein by reference.
- Aspects of the technology described herein relate to predicting treatment efficacy based on subject (e.g., patient) specific information such as a subject's (e.g., patient's) biomarkers.
- Some aspects of the technology described herein relate to determining therapy scores (for one or more potential treatments) and determining therapy scores before and after a treatment. Some aspects of the technology described herein relate to generating a graphical user interface (GUI) for visualizing therapy scores.
- Some aspects of the technology described herein relate to determining impact scores (for treatments). Some aspects of the technology described herein relate to generating a graphical user interface for visualizing impact scores.
- Some aspects of the technology described herein relate to determining normalized biomarker scores for a subject. Some aspects of the technology described herein relate to identifying the subject as a member of one or more cohorts using normalized biomarkers scores. Some aspects of the technology described herein relate to outputting such information (e.g., to one or more users). Some aspects of the technology described herein relate to potential inclusion or exclusion of a subject from a clinical trial.
- Correctly selecting one or more effective therapies for a subject (e.g., a patient) with cancer or determining the effectiveness of a treatment can be crucial for the survival and overall wellbeing of that subject. Advances in identifying effective therapies and understanding their effectiveness or otherwise aiding in personalized care of patients with cancer are needed.
- Provided herein, inter alia, are systems and methods for determining therapy scores for multiple therapies based on normalized biomarker scores. Such information, in some embodiments, is output to a user in a graphical user interface (GUI).
- Systems and methods for determining therapy scores for multiple therapies based on normalized biomarker scores comprises, in some embodiments, accessing sequence data for a subject, accessing biomarker information indicating distribution of values for biomarkers associated with multiple therapies, determining normalized biomarker scores for the subject using sequencing data and biomarker information, and determining therapy scores for the multiple therapies based on normalized biomarker scores.
- Provided herein, inter alia, are systems and methods for determining impact score for a candidate therapy using first and second normalized biomarker scores. Such information, in some embodiments, is output to a user in a graphical user interface (GUI).
- Systems and methods for determining impact score for a candidate therapy using first and second normalized biomarker scores comprises, in some embodiments, obtaining first sequencing data for a subject prior to administration of candidate therapy, obtaining second sequencing data for a subject subsequent to administration of candidate therapy, accessing biomarker information indicating distribution of values for a biomarker associated with the candidate therapy, determining first and second biomarker scores for the subject using first sequencing data, second sequencing data, and biomarker information, and determining impact score for the candidate therapy using first and second normalized biomarker scores.
- Provided herein, inter alia, are systems and methods for determining therapy scores for at least two selected therapies based on normalized biomarker scores for the at least three biomarkers. Such information, in some embodiments, is output to a user in a graphical user interface (GUI).
- Systems and methods for determining therapy scores for at least two selected therapies based on normalized biomarker scores for the at least three biomarkers comprises, in some embodiments, obtaining sequencing data for a subject, accessing biomarker information for at least three biomarkers associated with at least two selected therapies, determining first and second sets of normalized biomarker scores for the subject using sequencing data and biomarker information, and determining therapy scores for the at least two selected therapies based on normalized biomarker scores for the at least three biomarkers.
- Provided herein, inter alia, are systems and methods for obtaining first and second therapy scores for first and second therapies. Such information, in some embodiments, is output to a user in a graphical user interface (GUI).
- Systems and methods for obtaining first and second therapy scores for first and second therapies comprises, in some embodiments, obtaining sequence data for a subject, accessing biomarker information indicating distribution of values for biomarkers associated with multiple therapies, determining first and second sets of normalized biomarker scores for the subject using sequencing data and biomarker information, and obtaining first and second therapy scores for first and second therapies.
- Provided herein, inter alia, are systems and methods for identifying a subject as a member of a cohort using normalized biomarker scores. Such information, in some embodiments, is output to a user in a graphical user interface (GUI).
- Systems and methods for identifying a subject as a member of a cohort using normalized biomarker scores comprises, in some embodiments, obtaining sequencing data for a subject, accessing biomarker information indicating distribution of values for biomarkers associated with multiple therapies, determining normalized biomarker scores for the subject using sequencing data and biomarker information, and identifying the subject as a member of a cohort using normalized biomarker scores.
- In one aspect provided herein is a system, comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies, each of the therapy scores indicative of predicted response of the subject to administration of a respective therapy in the plurality of therapies.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies, each of the therapy scores indicative of predicted response of the subject to administration of a respective therapy in the plurality of therapies.
- In one aspect provided herein is a method, comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies, each of the therapy scores indicative of predicted response of the subject to administration of a respective therapy in the plurality of therapies.
- In one aspect provided herein is a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- In one aspect provided herein is a method, comprising: using at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- In one aspect provided herein is a system, comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information; a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized scores as input to the statistical model to obtain a second therapy score for the second therapy; generating a graphical user interface (GUI), wherein the GUI comprises: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized scores as input to the statistical model to obtain a second therapy score for the second therapy; generating a graphical user interface (GUT), wherein the GUI comprises: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- In one aspect provided herein is a method, comprising using the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized scores as input to the statistical model to obtain a second therapy score for the second therapy; generating a graphical user interface (GUI), wherein the GUI comprises: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- In one aspect provided herein is a system, comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized biomarker scores as input to the statistical model to obtain a second therapy score for the second therapy; wherein the plurality of therapies comprise at least two therapies selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and wherein the plurality of biomarkers associated with each of the plurality of therapies comprises at least three biomarkers selected from the group of biomarkers associated with the respective therapy in Table 2.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized biomarker scores as input to the statistical model to obtain a second therapy score for the second therapy; wherein the plurality of therapies comprise at least two therapies selected from the group consisting of: an ani-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and wherein the plurality of biomarkers associated with each of the plurality of therapies comprises at least three biomarkers selected from the group of biomarkers associated with the respective therapy in Table 2.
- In one aspect provided herein is a method, comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized biomarker scores as input to the statistical model to obtain a second therapy score for the second therapy; wherein the plurality of therapies comprise at least two therapies selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and wherein the plurality of biomarkers associated with each of the plurality of therapies comprises at least three biomarkers selected from the group of biomarkers associated with the respective therapy in Table 2.
- In one aspect provided herein is a system, comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one or more cohorts in which the subject is a member.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one or more cohorts in which the subject is a member.
- In one aspect a method comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one or more cohorts in which the subject is a member.
- Various aspects and embodiments will be described with reference to the following figures. The figures are not necessarily drawn to scale.
-
FIG. 1A is a diagram of an illustrative process for obtaining patient data and providing that data to a doctor, in accordance with some embodiments of the technology described herein. -
FIG. 1B is a block diagram of patient data that may be presented to a user, in accordance with some embodiments of the technology described herein. -
FIG. 1C is a graphical representation of patient data that may be presented to a user, in accordance with some embodiments of the technology described herein. -
FIG. 2A is a flow chart of an illustrative process for determining therapy scores for multiple therapies based normalized biomarker scores, in accordance with some embodiments of the technology described herein. -
FIG. 2B is a flow chart of an illustrative process for determining impact score for a candidate therapy using a first normalized biomarker score and a second normalized biomarker score, in accordance with some embodiments of the technology described herein. -
FIG. 2C is a flow chart of an illustrative process for determining therapy scores for that at least two selected therapies based on normalized biomarker scores for the at least three biomarkers, in accordance with some embodiments of the technology described herein. -
FIG. 2D is a flow chart of an illustrative process for obtaining first and second therapy scores for first and second therapies, in accordance with some embodiments of the technology described herein. -
FIG. 2E is a flow chart of an illustrative process for identifying a subject as a member of a cohort using normalized biomarker scores, in accordance with some embodiments of the technology described herein. -
FIG. 3 is a graphical representation of biomarker value distribution for a large patient cohort, as determined in accordance with some embodiments of the technology described herein. -
FIG. 4 is a graphical representation of patient therapy scores calculated as the sum of positive and negative biomarkers, in accordance with some embodiments of the technology described herein. -
FIG. 5 is a graphical representation of patient therapy scores calculated for multiple therapies for a patient that has been determined as responsive (Patient 1) or non-responsive (Patient 2) to an anti-PD1 therapy (Pembrolizumab), in accordance with some embodiments of the technology described herein. -
FIG. 6A is a screenshot presenting normalized biomarker values calculated for different immunotherapies, in accordance with some embodiments of the technology described herein. -
FIG. 6B is a screenshot presenting patient therapy scores for different immunotherapies calculated using normalized biomarker values, in accordance with some embodiments of the technology described herein. -
FIG. 6C is a screenshot presenting information related to biomarkers used to calculate patient therapy scores, in accordance with some embodiments of the technology described herein. -
FIG. 7A is a graphical representation of therapy scores calculated for patients treated with an anti-PD1 therapy (Pembrolizumab), in accordance with some embodiments of the technology described herein. Patients with progressive disease (PD) are shown in red, patients with stable disease (SD) are shown in light blue, and patients with complete response (CR) are shown in blue. -
FIG. 7B is a graphical representation of therapy scores calculated for patients treated with an anti-CTLA4 therapy (Ipilimumab), in accordance with some embodiments of the technology described herein. Patients with progressive disease (PD) are shown as a dark solid line, patients with stable disease (SD) are shown as a light grey striped line, and patients with partial response (PR) are shown in a dark grey striped line. -
FIG. 7C is a graphical representation of therapy scores calculated for patients treated with an anti-PD1 therapy (Pembrolizumab), in accordance with some embodiments of the technology described herein. Patients with progressive disease (PD) are shown as a dark solid line, patients with stable disease (SD) are shown as a light grey striped line, and patients with partial response (PR) are shown in a dark grey striped line. -
FIG. 8A is a graphical representation of therapy scores calculated without additional weight optimization in a machine learning-based optimization of biomarker importance, in accordance with some embodiments of the technology described herein. Patients with progressive disease (PD) are shown as a dark solid line, patients with stable disease (SD) are shown as a light grey striped line, and patients with partial response (PR) are shown in a dark grey striped line. -
FIG. 8B is a graphical representation of therapy scores calculated with machine-adapted weights, in accordance with some embodiments of the technology described herein. Patients with progressive disease (PD) are shown as a dark solid line, patients with stable disease (SD) are shown as a light grey striped line, and patients with partial response (PR) are shown in a dark grey striped line. -
FIG. 8C is a graphical representation of biomarker importance in terms of feature importance calculated with forest regression algorithms, in accordance with some embodiments of the technology described herein. -
FIG. 8D is a graphical representation of biomarker weights recalculated with a logistic regression model to improve prediction of therapy response, in accordance with some embodiments of the technology described herein. -
FIG. 9 is a graphic illustrating different types of screens that may be shown to a user of the software program. -
FIG. 10 is a screenshot presenting the selected patient's report including information related to the patient's sequencing data, the patient, and the patient's cancer. -
FIG. 11 is a screenshot presenting information related to anti-PD1 immunotherapy provided in response to selecting anti-PD1 immunotherapy (as shown by highlighting) in the immunotherapy biomarkers portion of the screen (as shown in the left panel). -
FIG. 12 is a screenshot presenting selection of mutational burden biomarker by a user. -
FIG. 13 is a screenshot presenting information relating to the mutational burden biomarker (as shown in the middle panel) provided in response to the user selecting the mutational burden biomarker. -
FIG. 14 is a screenshot presenting clinical trial data relating to anti-PD1 therapy effectivity in patients having stage IV metastatic melanoma (as shown in the right panel) provided in response to the user selecting anti-PD1 immunotherapy (as shown in the left panel). -
FIG. 15 is a block diagram of an illustrative computer system that may be used in implementing some embodiments of the technology described herein. - Currently, certain conventional therapy selection methods allow for selection of a therapy based on a single parameter (or biomarker) of an individual patient or tumor, the presence or absence of which is correlated with treatment response or patient survival. The inventors have appreciated that there are several problems with this type of single-parameter methodology. The first problem of such conventional therapy selection methods is their weak predictive power when evaluating potential candidate therapies. While a particular individual biomarker may be predictive of the efficacy of a candidate therapy for one cohort (or group) of subjects (e.g., patients), it may fail to do so for a second or further cohorts (or groups). A second biomarker may be predictive of the efficacy of the candidate therapy for a second or further cohorts (or groups) of subjects (e.g., patients), but fail to do so for the first cohort (or group). Thus, different individual biomarkers may suggest different courses of action. As a result, using a single biomarker to determine the efficacy of a candidate treatment is problematic for many patients. Even if a single biomarker having the highest correlation with response for a candidate treatment were chosen, it may still have a weak predictive capability without taking into account the full scope of each patient's case and personal condition.
- Another problem with conventional single-parameter methodology is the heterogeneity of a biomarker's values. Due to the variation in measurements of different clinics and clinical trials, potential biomarkers become incomparable between subjects (e.g., patients) from different hospitals or clinical settings. The biomarker values defined in one study could significantly differ from the results of the same measurements performed at a different site or on different equipment. While the relative meaning of a biomarker may remain unchanged—for example, a “high” biomarker value is bad or “low” value is good for predicting therapy efficacy—experimental cut-off or threshold values for “high” or “low” definitions often significantly vary among studies.
- The inventors have developed techniques for predicting the efficacy of therapies for a subject that address (e.g., mitigate or avoid) the above-described problems of conventional single-biomarker approaches. In particular, the inventors have developed techniques of predicting therapy efficacy using multiple biomarkers (e.g., biomarkers associated with positive therapeutic response or non-positive therapeutic response to a particular therapy or type of therapy). The inventors have appreciated that different biomarkers may have values in vastly different ranges. In order to use multiple such biomarkers in a single common quantitative framework for predicting therapy efficacy, the inventors have developed a technique for normalizing the values of the biomarkers relative to their variation in reference populations, thereby placing them on a common scale. The inventors have also recognized that comparing biomarker scores of a patient to those of other patients may be used to compute normalized biomarker scores. Further, such normalized biomarker scores may be utilized to more accurately predict a patient's response to a therapy. The inventors have specifically developed techniques for simultaneous analysis of the normalized biomarkers as described herein.
- Additionally, recent advances in personalized genomic sequencing and cancer genomic sequencing technologies have made it possible to obtain patient-specific information about cancer cells (e.g., tumor cells) and cancer microenvironments from one or more biological samples obtained from individual patients. This information can be used to determine a large number of parameters (or biomarkers) for each patient and, potentially, use this information to identify effective therapies and/or select one or more effective therapies for the subject (e.g., the patient). This information may also be used to determine how a subject (e.g., a patient) is responding over time to a treatment and, if necessary, to select a new therapy or therapies for the subject (e.g., the patient) as necessary. This information may also be used to determine whether the subject (e.g., the patient) should be included or excluded from participating in a clinical trial.
- Global comparison of different types and groupings of biomarkers using normalization as described herein was not known in the art, and the integration of such normalized biomarkers in a coherent and quantitative manner with therapy or impact scores calculated therefrom provide more accurate predictions (greater predictive capacity) of a patient's response to a therapy than might be seen by the use of any single marker or less complex combination of elements. The methods, systems, and graphical user interfaces (GUIs) based on such a wide variety of biomarkers as described herein are newly available and not previously described techniques or methods existed to perform the elements of these techniques. Further, techniques for combining various types of biomarkers in a single analytical tool had not been developed because these biomarkers were from different origins (i.e., different studies, hospitals, and treatment centers) and were of vastly differing scales.
- The inventors have recognized that several of the elements described herein add something more than what is well understood, routine, or conventional activity proposed by others in the field. These meaningful non-routine steps result in the improvements seen in the methods, systems, and GUIs described herein and include, but are not limited to: the normalization of different biomarker types to a common scale; the combination(s) of biomarker types provided herein; the determination of therapy scores from different biomarker types; technical improvements in analyses that allow for more accurate prediction of a patient's response to a therapy and resulting improvements in outcome for the patient; and the creation of improved graphical user interfaces to aid in the selection of a therapy.
- Therefore, aspects of the technology described herein relate to systems and methods and for predicting a patient's response to a therapy based on patient specific information such as a patient's biomarker values. In some embodiments, predicting a patient's response to a therapy comprises determining normalized biomarker scores (also described as “normalized scores”) using sequencing data and biomarker information. In some embodiments, predicting a patient's response to a therapy comprises determining therapy scores for the multiple therapies based on normalized biomarker scores. A therapy score for a therapy is a numerical value that may provide a quantitative measure of the therapy's predicted efficacy in treating a subject. In some embodiments, determining a patient's response to a therapy comprises determining an impact score based on normalized biomarker scores. An impact score for a therapy is a numerical value that may provide a quantitative measure of the therapy's current efficacy (impact) in treating a subject.
- Such methods and systems may be useful for clinical purposes including, for example, selecting a treatment, evaluating suitability of a patient for participating in a clinical trial, or determining a course of treatment for a subject (e.g., a patient).
- The methods and systems described herein may also be useful for non-clinical applications including (as a non-limiting example) research purposes such as, e.g., studying the biological pathways and/or biological processes targeted by a therapy, and developing new therapies for cancer based on such studies.
- Further, systems which present this information in a comprehensive and useable format will be needed to facilitate treatment of patients with such conditions. Therefore, provided herein are systems and methods for analyzing patient specific information that result in a prediction of a patient's response or lack thereof to a treatment.
- Such an analysis takes into consideration a global view of patient information to make a prediction regarding the patient's response to a therapy that is well-informed and comprehensive. The analysis described herein, in some embodiments, is a global analysis of patient specific information. Certain aspects of the described methods take into account biological data generated from analysis of at least one biological sample of a subject. Other aspects of the described methods take into account patient specific information related to the overall health and/or lifestyle of a patient (e.g., personal habits, environmental factors) that may play a role in whether a patient responds to a therapy.
- Generally, techniques described herein provide for improvements over conventional computer-implemented techniques for analysis of medical data such as evaluation of expression data (e.g., RNA expression data) and determining whether one or more therapies (e.g., targeted therapies, radiotherapies, and/or immunotherapies) will be effective in treating the subject. Such improvements include, but are not limited to, improvements in predictive power regarding the effectiveness of candidate treatments for a subject over conventional single biomarker treatments. Additionally, some embodiments of the technology provided herein are directed to graphical user interfaces that present oncological data in a new way which is compact and highly informative. These graphical user interfaces not only reduce the cognitive load on a user (e.g., a doctor or other medical professional) working with them, but may serve to reduce clinician errors and improve the functionality of a computer by providing all needed information in a single interactive interface. This could eliminate the need for a user (e.g., a clinician) to consult different sources of information (e.g., view multiple different webpages, use multiple different application programs, etc.), which would otherwise place an additional burden on the processing, memory, and communications resources of the computer(s) used by such a user (e.g., a clinician).
- The methods described are based on in part on the analysis of anthropometric, clinical, tumor, and/or cancerous cell microenvironment parameters, and tumor and/or cancerous cell parameters of a subject (e.g., a patient), along with accompanying disease information. For such analyses, sequence data such as that from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy, or from other tissues of the patient are suitable although any type of sequence data may be used. Additional data concerning other patient, cancerous cell, or tumor parameters, or microenvironment parameters may also be considered including, but not limited to: tumor and/or cancerous cell proteomic analysis; immunohistochemistry staining; flow cytometry; standard clinical measurements of blood, urine and other biological fluids; biopsies of one or more tumors and organs; images obtained by any methods, including X-ray, ultrasonic, sonic, or magnetic resonance imaging scintillation studies, etc. In these terms, all features that distinguish one patient from another including, but not limited to, disease stage, sex, age, tumor mutations, cancerous cell mutations, blood analysis, IHC of biopsy, etc. are called patient parameters and may be included in the algorithm. The parameters of the subject (e.g., the patient), the type of tumor, or the type of cancerous cell may have been identified in group clinical trials that were published in scientific journals or actively used in clinically approved analyses, guidelines of treatment options (FDA, NIH, NCCN, CPIC, etc.) or elsewhere. These parameters are biomarkers, the presence or absence of which and/or levels of which may be statistically significantly correlated (e.g., the correlation may be at least a threshold amount away from zero) with treatment response or patient survival.
- Certain techniques described herein are designed to use any reliable and available information about discovered biomarkers to simultaneously analyze individual biomarkers of the patient and may use any number of pre-defined biomarker combinations. This method generally considers several parameters concerning the patient and/or the cancerous tissues and/or cells of the patient and does not classify the patient to a one-biomarker group, such as high or low PDL1 expression. Certain techniques described herein may be based on the simultaneous analysis of tens or hundreds of biomarkers.
- In some embodiments, the techniques described herein provide a way to generate “thresholds” for pre-defined biomarkers based on (e.g., large volumes of) data obtained from large numbers of patients, such as TCGA, ICGC, Human Protein Atlas, etc., allowing for the creation of a normalized score for each of the biomarkers. Combinations of normalized biomarker scores for the patient may be used to analyze one more defined therapies (creating therapy scores) providing information that allows the selection of one or more therapies for each patient based on their personal parameters.
- Aspects of the present disclosure relate to systems and methods for predicting efficacy of a cancer treatment from a plurality of biomarkers. As used herein, the term “biomarker” refers to any information (or any parameter) of a biomolecule (e.g., a gene or a protein), a cancer (e.g., tumor type) or a subject (e.g., age of a subject) that may be used to predict an effect of a therapy or lack thereof in the subject. Accordingly, “biomarker information” or “biomarker value” as used herein, refers to any information relating to a biomarker. As a non-limiting example, if a biomarker is age, a biomarker value (e.g., information about the biomarker) may be 32 for a patient that is 32 years of age.
- A biomarker as described herein may be associated with at least one therapy and/or at least one cancer. As used herein, the term “associated with” indicates that a biomarker has been found to be relevant (e.g., in one or more studies such as those described in a paper or journal article) to and/or involved with the associated therapy and/or the associated cancer. It should be appreciated that a biomarker, in some embodiments, may be directly linked to a therapy and/or cancer or indirectly linked to a therapy and/or a cancer (e.g., that the biomarker has been found to directly or indirectly effect or modulate a biological process related to the therapy and/or the cancer). As a set of non-limiting examples, biomarkers for use with the methods and systems described herein may include any group or subset of biomarkers listed herein, including those listed in the Tables (e.g., in Table 2). Such a group or subset of biomarkers may include at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 200, at least 300, at least 400, at least 500, at least 600, at least 700, at least 800, at least 900, or at least 1000 biomarkers. Such a group or subset of biomarkers may include up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, up to 100, up to 200, up to 300, up to 400, up to 500, up to 600, up to 700, up to 800, up to 900, or up to 1000 biomarkers.
- A biomarker as described herein, in some embodiments, may be associated with multiple therapies. In some embodiments, a biomarker may be associated with at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 different therapies. In some embodiments, a biomarker may be associated with up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, or up to 100 different therapies.
- A biomarker as described herein, in some embodiments, may be associated with multiple cancers. In some embodiments, a biomarker may be associated with at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 different cancers. In some embodiments, a biomarker may be associated with up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 20, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, or up to 100 different cancers.
- Biomarkers as provided herein may be associated with any biomolecule. Examples of a biomolecule include, but are not limited to, a growth factor, a hormone, a steroid, a saccharide, a lipid, a heterocyclic compound, an elementary compound (e.g., iron), a metabolite, a vitamin, a neurotransmitter, and fatty acids. Such biomarkers may be referred to by the biomolecule that they are associated with. For example, a biomarker associated with a saccharide may be referred to as a saccharide biomarker, a biomarker associated with a lipid may be referred to as a lipid biomarker; a biomarker associated with a heterocyclic compound may be referred to as a heterocyclic biomarker, and a biomarker associated with an elementary compound may be referred to as an elementary compound biomarker.
- A “genetic biomarker,” as used herein, is a biomarker associated with a gene or any product thereof (e.g., RNA, protein). Examples of a genetic biomarker include, but are not limited to, a gene expression level (e.g., an increased expression level or a decreased expression level), a gene mutation, a gene insertion, a gene deletion, a gene fusion, a single nucleotide polymorphism (SNPs), and a gene copy number variation (CNV).
- A genetic biomarker as described herein may be associated with any gene. In some embodiments, genes are group by a related function and/or other property. Examples of gene groups include, but are not limited to, the fibroblasts group, the angiogenesis group, the tumor properties group, the anti-tumor immune microenvironment group, the tumor-promoting immune microenvironment group, the cancer associated fibroblasts group, the proliferation rate group, the PI3K/AKT/mTOR signaling group, the RAS/RAF/MEK signaling group, the receptor tyrosine kinases expression group, the tumor suppressors group, the metastasis signature group, the anti-metastatic factors group, the mutation status group, the antigen presentation group, the cytotoxic T and NK cells group, the B cells group, the anti-tumor microenvironment group, the checkpoint inhibition group, the Treg group, the MDSC group, the granulocytes group, the tumor-promotive immune group, the receptor tyrosine kinases expression group, the growth factors group, the tumor suppressors group, the metastasis signature group, the anti-metastatic factors group, the mutation status group, the MHCI group, the MHCII group, the coactivation molecules group, the effector cells group, the NK cells group, the T cell traffic group, the T cells group, the M1 signatures group, the Th1 signature group, the antitumor cytokines group, the checkpoint inhibition group, the M2 signature group, the Th2 signature group, the protumor cytokines group, and the complement inhibition group.
- In some embodiments, a genetic biomarker may be associated with some (e.g., at least three) genes from one or more of the following groups: the fibroblasts group: LGALS1, COL1A1, COL1A2, COL4A1, COL5A1, TGFB1, TGFB2, TGFB3, ACTA2, FGF2, FAP, LRP1, CD248, COL6A1, COL6A2, and COL6A3; the angiogenesis group: VEGFA, VEGFB, VEGFC, PDGFC, CXCL8, CXCR2, FLT1, PIGF, CXCL5, KDR, ANGPT1, ANGPT2, TEK, VWF, CDH5, NOS3, KDR, VCAM1, MMRN1, LDHA, HIF1A, EPAS1, CA9, SPP1, LOX, SLC2A1, and LAMP3; the tumor properties group: MK167. ESCO2, CETN3, CDK2, CCND1, CCNE1, AURKA, AURKB, CDK4, CDK6, PRC1, E2F1, MYBL2, BUB1, PLK1, CCNB1, MCM2, MCM6, PIK3CA, PIK3CB, PIK3CG, PIK3CD, AKT1, MTOR, PTEN, PRKCA, AKT2, AKT3, BRAF, FNTA, FNTB, MAP2K1, MAP2K2, MKNK1, MKNK2, ALK, AXL, KIT, EGFR, ERBB2, FLT3, MET, NTRK1, FGFR1, FGFR2, FGFR3, ERBB4, ERBB3, BCR-ABL, PDGFRA, PDGFRB, NGF, CSF3, CSF2, FGF7, IGF1, IGF2, IL7, FGF2, TP53, SIK1, PTEN, DCN, MTAP, AIM2, RB1, ESRP1, CTSL, HOXAL, SMARCA4, SNAI2, TWIST1, NEDD9, PAPPA, HPSE, KISS1, ADGRG1, BRMS1, TCF21, CDH1, PCDH10, NCAM1, MITF, APC, ARID1A, ATM, ATRX, BAP1, BRAF, BRCA2, CDH1, CDKN2A, CTCF, CTNNB1, DNMT3A, EGFR, FBXW7, FLT3, GATA3, HRAS, IDH1, KRAS, MAP3K1. MTOR. NAV3, NCOR1, NF1, NOTCH1, NPM1, NRAS, PBRM1, PIK3CA, PIK3R1, PTEN, RB1, RUNX1, SETD2, STAG2, TAF1, TP53, and VHL; the anti-tumor immune microenvironment group: HLA-A, HLA-B, HLA-C, B2M, TAP1, TAP2, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DPB2, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DMB, HLA-DQB1, HLA-DQA1, HLA-DRB5, HLA-DQA2, HLA-DQB2, HLA-DRB6, CD80, CD86, CD40, CD83, TNFRSF4, ICOSLG, CD28, IFNG, GZMA, GZMB, PRF1, LCK, GZMK, ZAP70, ONLY, FASLG, TBX21, EOMES, CD8A, CD8B, NKG7, CD160, CD244, NCR1, KLRC2, KLRK1, CD226, GZMH, ONLY, IFNG, KIR2DL4, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, KIR2DS5, CXCL9, CXCL0, CXCR3, CX3CL1, CCR7, CXCL11, CCL21, CCL2, CCL3, CCL4, CCL5, EOMES, TBX21, ITK, CD3D, CD3E, CD3G, TRAC, TRBC1, TRBC2, LCK, UBASH3A, TRAT1, CD19. MS4A1, TNFRSF13C, CD27, CD24, CR2, TNFRSF17, TNFRSF13B, CD22, CD79A, CD79B, BLK, NOS2, IL12A, IL12B, IL23A, TNF, IL1B, SOCS3, IFNG, IL2, CD40LG, IL15, CD27, TBX21, LTA, IL21, HMGB1, TNF, IFNB1, IFNA2, CCL3, TNFSF10, and FASLG; the tumor-promoting immune microenvironment group: PDCD1, CD274, CTLA4, LAG3, PDCD1LG2, BTLA, HAVCR2, VSIR, CXCL12, TGFB1, TGFB2, TGFB3, FOXP3, CTLA4, IL10, TNFRSF1B, CCL17, CXCR4, CCR4, CCL22, CCL1, CCL2, CCL5, CXCL13, CCL28, IDO1, ARG1, IL4R, IL10, TGFB1, TGFB2, TGFB3, NOS2, CYBB, CXCR4, CD33, CXCL1, CXCL5, CCL2, CCL4, CCL8, CCR2, CCL3, CCL5, CSF1, CXCL8, CXCL8, CXCL2, CXCL1, CCL11, CCL24, KITLG, CCL5, CXCL5, CCR3, CCL26, PRG2, EPX, RNASE2, RNASE3, IL5RA, GATA1, SIGLEC8, PRG3, CMA1, TPSAB1, MS4A2, CPA3, IL4, IL5, IL13, SIGLEC8, MPO, ELANE, PRTN3, CTSG, IL10, VEGFA, TGFB1, IDO1, PTGES, MRC1, CSF1, LRP1, ARG1, PTGS1, MSR1, CD163, CSF1R, IL4, IL5, IL13, IL10, IL25, GATA3, IL10, TGFB1, TGFB2, TGFB3, IL22, MIF, CFD, CF1, CD55, CD46, and CR1; the cancer associated fibroblasts group: LGALS1, COL1A1, COL1A2, COL4A1, COL5A1, TGFB1, TGFB2, TGFB3, ACTA2, FGF2, FAP, LRP1, CD248, COL6A1, COL6A2, and COL6A3; the angiogenesis group: VEGFA, VEGFB, VEGFC, PDGFC, CXCL8, CXCR2, FLT1, PIGF, CXCL5, KDR, ANGPT1, ANGPT2, TEK, VWF, CDH5, NOS3, KDR, VCAM1, MMRN1, LDHA, HIF1A, EPAS1, CA9, SPP1, LOX, SLC2A1, and LAMP3; the proliferation rate group: MK167, ESCO2, CETN3, CDK2, CCND1, CCNE1, AURKA, AURKB, CDK4, CDK6, PRC1, E2F1, MYBL2, BUB1, PLK1, CCNB1, MCM2, and MCM6; the PI3K/AKT/mTOR signaling group: PIK3CA, PIK3CB, PIK3CG, PIK3CD, AKT1, MTOR, PTEN, PRKCA, AKT2, and AKT3; the RAS/RAF/MEK signaling group: BRAF, FNTA, FNTB, MAP2K1. MAP2K2, MKNK1, and MKNK2; the receptor tyrosine kinases expression group: ALK, AXL, KIT, EGFR, ERBB2, FLT3, MET, NTRK1, FGFR1, FGFR2, FGFR3, ERBB4, ERBB3, BCR-ABL, PDGFRA, and PDGFRB; the tumor suppressors group: TP53, SIK1, PTEN, DCN, MTAP, AIM2, and RB1; the metastasis signature group: ESRP1, CTSL, HOXA1, SMARCA4, SNAI2, TWIST1, NEDD9, PAPPA, and HPSE; the anti-metastatic factors group: KISS1, ADGRG1, BRMS1, TCF21, CDH1, PCDH10, NCAM1, and MITF; the mutation status group: APC, ARID1A, ATM, ATRX, BAP1, BRAF, BRCA2, CDH1, CDKN2A, CTCF, CTNNB1, DNMT3A, EGFR, FBXW7, FLT3, GATA3, HRAS, IDH1, KRAS, MAP3K1, MTOR, NAV3, NCOR1, NF1, NOTCH1, NPM1, NRAS, PBRM1, PIK3CA, PIK3R1, PTEN, RB1, RUNX1, SETD2, STAG2, TAF1, TP53, and VHL; the antigen presentation group: HLA-A, HLA-B, HLA-C, B2M, TAP1, TAP2, HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DPB2, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DMB, HLA-DQB1, HLA-DQA1, HLA-DRB5, HLA-DQA2, HLA-DQB2, HLA-DRB6, CD80, CD86, CD40, CD83, TNFRSF4, ICOSLG, and CD28; the cytotoxic T and NK cells group: IFNG, GZMA, GZMB, PRF1, LCK, GZMK, ZAP70, GNLY, FASLG, TBX21, EOMES, CD8A, CD8B, NKG7, CD160, CD244, NCR1, KLRC2, KLRK1, CD226, GZMH, GNLY, IFNG, KIR2DL4, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, K1R2DS5, CXCL9, CXCL10, CXCR3, CX3CL1, CCR7, CXCL11, CCL21. CCL2, CCL3, CCL4, CCL5, EOMES, TBX21, ITK, CD3D, CD3E, CD3G, TRAC, TRBC1, TRBC2, LCK, UBASH3A, and TRAT1; the B cells group: CD19, MS4A1, TNFRSF13C, CD27, CD24, CR2, TNFRSF17, TNFRSF13B, CD22. CD79A, CD79B, and BLK; the anti-tumor microenvironment group: NOS2, IL12A, IL12B, IL23A, TNF, IL1B, SOCS3, IFNG, IL2, CD40LG, IL15, CD27, TBX21, LTA, IL21, HMGB1, TNF, IFNB1, IFNA2, CCL3, TNFSF10, and FASLG; the checkpoint inhibition group: PDCD1, CD274, CTLA4, LAG3, PDCD1LG2, BTLA, HAVCR2, and VSIR; the Treg group: CXCL12, TGFB1, TGFB2, TGFB3, FOXP3, CTLA4, IL10, TNFRSF1B, CCL17, CXCR4, CCR4, CCL22, CCL1, CCL2, CCL5, CXCL13, and CCL28; the MDSC group: IDO1, ARG1, IL4R, IL10, TGFB1, TGFB2, TGFB3, NOS2, CYBB, CXCR4, CD33, CXCL1, CXCL5, CCL2, CCL4, CCL8, CCR2, CCL3, CCL5, CSF1, and CXCL8; the granulocytes group: CXCL8, CXCL2, CXCL1, CCL11, CCL24, KITLG, CCL5, CXCL5, CCR3, CCL26, PRG2, EPX, RNASE2, RNASE3, IL5RA, GATA1, SIGLEC8, PRG3, CMA1, TPSAB1, MS4A2, CPA3, IL4, IL5, IL13, SIGLEC8, MPO, ELANE, PRTN3, and CTSG; the tumor-promotive immune group: IL10, VEGFA, TGFB1, IDO1, PTGES, MRC1, CSF1, LRP1, ARG1, PTGS1, MSR1, CD163, CSF1R, IL4, IL5, IL13, IL10, IL25, GATA3, IL10, TGFB1, TGFB2, TGFB3, IL22, MIF, CFD, CF1, CD55, CD46, and CR1; the receptor tyrosine kinases expression group: ALK, AXL, KIT, EGFR, ERBB2, FLT3, MET, NTRK1, FGFR1, FGFR2, FGFR3, ERBB4, ERBB3, BCR-ABL, PDGFRA, and PDGFRB; the growth factors group: NGF, CSF3, CSF2, FGF7, IGF1, IGF2, IL7, and FGF2; the tumor suppressors group: TP53, SIK1, PTEN. DCN, MTAP, AIM2, and RB1; the metastasis signature group: ESRP1, CTSL, HOXA1, SMARCA4, SNA12, TWIST1, NEDD9, PAPPA, and HPSE; the anti-metastatic factors group: KISS1, ADGRG1, BRMS1, TCF21, CDH1, PCDH10, NCAM1, and MITF; the mutation status group: APC, ARID1A, ATM, ATRX, BAP1, BRAF, BRCA2, CDH1, CDKN2A, CTCF, CTNNB1, DNMT3A, EGFR, FBXW7, FLT3, GATA3, HRAS, IDH1, KRAS, MAP3K1, MTOR, NAV3, NCOR1, NF1, NOTCH1, NPM1, NRAS, PBRM1, PIK3CA, PTK3R1, PTEN, RB1, RUNX1, SETD2, STAG2, TAF1, TP53, and VHL; the MHCI group: HLA-A, HLA-B, HLA-C, B2M, TAP1, and TAP2; the MHCII group: HLA-DRA, HLA-DRB1, HLA-DOB, HLA-DPB2, HLA-DMA, HLA-DOA, HLA-DPA1, HLA-DPB1, HLA-DMB, HLA-DQB1, HLA-DQA1. HLA-DRB5, HLA-DQA2, HLA-DQB2, and HLA-DRB6; the coactivation molecules group: CD80, CD86, CD40, CD83, TNFRSF4, ICOSLG, and CD28; the effector cells group: IFNG, GZMA, GZMB, PRF1, LCK, GZMK, ZAP70, GNLY, FASLG, TBX21, EOMES, CD8A, and CD8B; the NK cells group: NKG7, CD160, CD244, NCR1, KLRC2, KLRK1, CD226, GZMH, GNLY, IFNG, KIR2DL4, KIR2DS1, KIR2DS2, KIR2DS3, KIR2DS4, and KIR2DS5; the T cell traffic group: CXCL9, CXCL10, CXCR3, CX3CL1, CCR7, CXCL11, CCL21, CCL2, CCL3, CCL4, and CCL5; the T cells group: EOMES, TBX21, ITK, CD3D, CD3E, CD3G, TRAC, TRBC1, TRBC2, LCK, UBASH3A, and TRAT1; the M1 signatures group: NOS2, IL12A, IL12B, IL23A, TNF, IL1B, and SOCS3; the Th1 signature group: IFNG, IL2, CD40LG, IL15, CD27, TBX21, LTA, and IL21; the antitumor cytokines group: HMGB1, TNF, IFNB1, IFNA2, CCL3, TNFSF10, and FASLG; the M2 signature group: IL10, VEGFA, TGFB1, IDO1, PTGES, MRC1, CSF1, LRP1, ARG1, PTGS1, MSR1, CD163, and CSF1R; the Th2 signature group: IL4, IL5, IL13, IL10, IL25, and GATA3; the protumor cytokines group: IL10, TGFB1, TGFB2, TGFB3, IL22, and MIF; and the complement inhibition group: CFD, CF1, CD55, CD46, and CR1.
- A “protein biomarker,” as used herein, is a biomarker associated with a protein. Examples of a protein biomarker include, but are not limited to, a protein expression level (e.g., an increased expression level or a decreased expression level), a protein activity level (e.g., an increased activity level or a decreased activity level), a protein mutation, and a protein truncation.
- A protein biomarker as described herein may associated with any protein. Examples of proteins related to protein biomarkers include, but are not limited to, interferons, cytotoxic proteins, enzymes, cell adhesion proteins, extracellular matrix proteins, transcription factor proteins, intracellular signaling proteins, cytokines, chemokines, chemokine receptors, and interleukins. Such biomarkers may be referred to by the biomolecule for which they are related to, for example, interferon biomarker, cytotoxic protein biomarker, enzyme biomarker, cell adhesion protein biomarker, extracellular matrix protein biomarker, transcription factor protein biomarker, intracellular signaling protein biomarker, cytokine biomarker, chemokine biomarker, chemokine receptor biomarker, and interleukin biomarker. Such protein biomarkers may include products of, for example, any of the genes listed or referred to herein.
- A “cellular biomarker,” as used herein, is a biomarker associated with a cell. Examples of cellular biomarkers include, but are not limited to, numbers of types of one or more cells, percentage of one or more types of cells, location of one or more cells, and structure or morphology of one or more cells.
- A cellular biomarker as described herein may be associated with any cell. Examples of cells include, but are not limited to, malignant cancer cells, leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- An “expression biomarker,” as used herein, is a biomarker associated with an expression of a gene or a product thereof (e.g., RNA, protein). Examples of expression biomarkers include, but are not limited to, an increased expression level of a gene or product thereof, a decreased expression level of a gene or product thereof, expression of a truncated gene or product thereof, and expression of a mutated gene or product thereof.
- By comparing the expression level of a biomarker in a sample obtained from a subject to a reference (or control), it can be determined whether the subject has an altered expression level (e.g., increased or decreased) as compared to the reference (or control). For example, if the level of a biomarker in a sample from a subject deviates (e.g., is increased or decreased) from the reference value (by e.g., 1%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 300%, 400%, 500% or more from a reference value), the biomarker might be identified as an expression biomarker.
- An “imaging biomarker,” as used herein, is a biomarker associated with imaging data. Examples of imaging biomarkers include, but are not limited to, expression levels obtained from imaging data, numbers of types of one or more cells obtained from imaging data, and cancer location and/or progression obtained from imaging data.
- An imaging biomarker as described herein may be associated with any imaging data. Examples of imaging data include, but are not limited to, histological imaging data, immunohistological imaging data, magnetic resonance imaging (MRI) data, ultrasound data, and x-ray data.
- A “disease-state biomarker,” as used herein, is a biomarker associated with a state of a disease (e.g., cancer). Examples of disease-state biomarkers include, but are not limited to, metastasis status (e.g., absence or presence of metastasis), remission status (e.g., number of previous remissions, current remission), disease progression (e.g., low, moderate, or high disease progression), and cancer stage (e.g.,
stage 1,stage 2,stage 3, or stage 4). - Biomarkers as used herein encompasses any patient specific information that may be used to predict that patient's response to a therapy. For example, a personal habit of a patient (e.g., smoking) may be used as a biomarker to predict whether the patient is a responder or non-responder to a therapy.
- A “personal habit biomarker,” as used herein, is a biomarker associated with a personal habit of a subject. Examples of personal habit biomarkers include, but are not limited to, smoking (e.g., status as a smoker or non-smoker), frequency of exercise, alcohol use (e.g., low, moderate, high use of alcohol), and drug use (e.g., low, moderate, high use of drugs).
- In another example, a cultural or environmental factor experienced by a patient may play a role in whether the patient responds to a therapy. Such factors are used in systems and methods described herein to predict a patient's response to a therapy.
- An “anthropological biomarker,” as used herein, is a biomarker associated with a culture and/or an environment of a subject. Examples of anthropological biomarkers include, but are not limited to, stress (e.g., low, moderate, or high stress levels), economic status (e.g., low, moderate, or high economic status), mental health (e.g., depression or anxiety), and relationship status (e.g., married, single, divorced, or widowed).
- Aspects of the present disclosure provide systems and methods that normalize biomarker scores to a common scale, thereby allowing comparison of biomarker scores across different cell populations and/or among different subjects.
- Normalized biomarker scores may be determined for any number of biomarkers as described herein. As used herein, the term “normalized biomarker score” refers to a biomarker value that has been adjusted (e.g., normalized) to a common scale according to the techniques described herein.
- In some embodiments, biomarker values are normalized to create normalized biomarker scores based on a respective distribution of values for each biomarker in a reference subset of biomarkers. In some embodiments, the reference subset of biomarkers comprises biomarker information from any number of reference subjects. In one embodiment, a “reference subset” is a subset of biomarkers from one or more reference subjects, the values of which may be used to normalize a biomarker of a subject.
- As a non-limiting example, data may be available for up to 4,000 biomarkers for a group of subjects. In this group of 4,000 biomarkers, 1,000 biomarkers may be associated with a particular therapy (thus creating a reference subset of 1,000 biomarkers). If, for a particular subject being analyzed using the methods and systems described herein, values for 723 of these biomarkers are available (thus creating a subject subset of 723 biomarkers), a normalized biomarker score for each of the 723 biomarkers may be computed using the distribution of values for each particular biomarker. As another non-limiting example, in this group of 4,000 biomarkers, 10 biomarkers may be associated with a particular therapy (thus creating a reference subset of 10 biomarkers). If, for a particular subject being analyzed using the methods and systems described herein, values for 7 of these biomarkers are available (thus creating a subject subset of 7 biomarkers), a normalized biomarker score for each of the 7 biomarkers may be computed using the distribution of values for each particular biomarker.
- In some embodiments, the reference subset of biomarkers comprises biomarker information from any number of subjects. In some embodiments, the reference subset of biomarkers comprises biomarker information from at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 subjects. In some embodiments, the reference subset of biomarkers comprises biomarker information from up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 subjects.
- A reference subset of biomarkers may comprise any number of biomarkers. In some embodiments, the reference subset of biomarkers comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 biomarkers. In some embodiments, the reference subset of biomarkers comprises up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 biomarkers.
- In some embodiments, biomarker values are normalized to create normalized biomarker scores based on a respective distribution of values for each biomarker in a subject subset of biomarkers. As used herein, the “subject subset” of biomarkers comprises biomarker information from a single subject. A subject subset of biomarkers may comprise any number of biomarkers. In some embodiments, the subject subset of biomarkers comprises at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 biomarkers. In some embodiments, the subject subset of biomarkers comprises up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 biomarkers. In some embodiments, the subject subset of biomarkers is identical to the reference subset of biomarkers (i.e., for a given calculation, system, or method described herein).
- Systems and methods described herein provide for determining any number of normalized biomarker scores using sequencing data and biomarker information. In some embodiments, systems and methods described herein provide for determining at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 normalized biomarker scores. In some embodiments, systems and methods described herein provide for determining up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 normalized biomarker scores.
- Systems and methods described herein, in some embodiments, provide for determining normalized biomarker scores for biomarkers associated with a particular therapy. In some embodiments, systems and methods described herein provide for determining normalized biomarker scores for at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 55, at least 60, at least 65, at least 70, at least 75, at least 80, at least 85, at least 90, at least 95, at least 100, at least 200, at least 300, at least 400, at least 500, or at least 1000 biomarkers associated with a particular therapy. In some embodiments, systems and methods described herein provide for determining normalized biomarker scores for up to 1, up to 2, up to 3, up to 4, up to 5, up to 6, up to 7, up to 8, up to 9, up to 10, up to 11, up to 12, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 25, up to 30, up to 35, up to 40, up to 45, up to 50, up to 55, up to 60, up to 65, up to 70, up to 75, up to 80, up to 85, up to 90, up to 95, up to 100, up to 200, up to 300, up to 400, up to 500, or up to 1000 biomarkers associated with a particular therapy.
- Systems and methods for normalization of biomarkers as described herein may be applied to biomarkers for any cancer (e.g., any tumor). Exemplary cancers include, but are not limited to, adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, colon adenocarcinoma, esophageal carcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, thyroid carcinoma, uterine corpus endometrial carcinoma, any type of lymphoma, leukemia, and cholangiocarcinoma.
- Biomarker information as described herein may be obtained from a variety of sources. In some embodiments, biomarker information may be obtained by analyzing a biological sample from a patient. The biological sample may be analyzed prior to performance of the methods described herein for predicting the efficacy of one or more treatments for the patient. In some such embodiments, data obtained from the biological sample may stored (e.g., in a database) and accessed during performance of the techniques described herein for predicting the efficacy of one or more treatments for the patient. In some embodiments, biomarker information is obtained from a database containing biomarker information for at least one patient.
- Any biological sample from a subject (i.e., a patient or individual) may be analyzed as described herein to obtain biomarker information. In some embodiments, the biological sample may be any sample from a subject known or suspected of having cancerous cells or pre-cancerous cells.
- The biological sample may be from any source in the subject's body including, but not limited to, any fluid [such as blood (e.g., whole blood, blood serum, or blood plasma), saliva, tears, synovial fluid, cerebrospinal fluid, pleural fluid, pericardial fluid, ascitic fluid, and/or urine], hair, skin (including portions of the epidermis, dermis, and/or hypodermis), oropharynx, laryngopharynx, esophagus, stomach, bronchus, salivary gland, tongue, oral cavity, nasal cavity, vaginal cavity, anal cavity, bone, bone marrow, brain, thymus, spleen, small intestine, appendix, colon, rectum, anus, liver, biliary tract, pancreas, kidney, ureter, bladder, urethra, uterus, vagina, vulva, ovary, cervix, scrotum, penis, prostate, testicle, seminal vesicles, and/or any type of tissue (e.g., muscle tissue, epithelial tissue, connective tissue, or nervous tissue).
- The biological sample may be any type of sample including, for example, a sample of a bodily fluid, one or more cells, a piece of tissue, or some or all of an organ. In certain embodiments, one sample will be taken from a subject for analysis. In some embodiments, more than one (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more) samples may be taken from a subject for analysis. In some embodiments, one sample from a subject will be analyzed. In certain embodiments, more than one (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or more) samples may be analyzed. If more than one sample from a subject is analyzed, the samples may be procured at the same time (e.g., more than one sample may be taken in the same procedure), or the samples may be taken at different times (e.g., during a different procedure including a
procedure - Any of the biological samples described herein may be obtained from the subject using any known technique. In some embodiments, the biological sample may be obtained from a surgical procedure (e.g., laparoscopic surgery, microscopically controlled surgery, or endoscopy), bone marrow biopsy, punch biopsy, endoscopic biopsy, or needle biopsy (e.g., a fine-needle aspiration, core needle biopsy, vacuum-assisted biopsy, or image-guided biopsy). In some embodiments, each of the at least one biological samples is a bodily fluid sample, a cell sample, or a tissue biopsy.
- In some embodiments, one or more than one cell (i.e., a cell sample) may be obtained from a subject using a scrape or brush method. The cell sample may be obtained from any area in or from the body of a subject including, for example, from one or more of the following areas: the cervix, esophagus, stomach, bronchus, or oral cavity. In some embodiments, one or more than one piece of tissue (e.g., a tissue biopsy) from a subject may be used. In certain embodiments, the tissue biopsy may comprise one or more than one (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more than 10) samples from one or more tumors or tissues known or suspected of having cancerous cells.
- Systems and methods described herein are based, at least in part, on the identification and characterization of certain biomarkers of a patient and/or the patient's cancer. Such information may be obtained from a biological sample of the subject (e.g., the patient) as described herein.
- Any type of analysis may be performed on a biological sample from a subject. In some embodiments, a blood analysis is performed on a biological sample from a subject. In some embodiments, a cytometry analysis is performed on a biological sample from a subject. In some embodiments, a histological analysis is performed on a biological sample from a subject. In some embodiments, a immunohistological analysis is performed on a biological sample from a subject.
- Any type of sequencing data may be obtained from a biological sample of a subject. In some embodiments, the sequencing data is DNA sequencing data. In some embodiments, the sequencing data is RNA sequencing data. In some embodiments, the sequencing data is proteome sequencing data.
- Such sequencing data may be obtained by any known technique. In some embodiments, the sequencing data is obtained from whole genome sequencing (WGS). In some embodiments, the sequencing data is obtained from whole exome sequencing (WES). In some embodiments, the sequencing data is obtained from whole transcriptome sequencing. In some embodiments, the sequencing data is obtained from mRNA sequencing. In some embodiments, the sequencing data is obtained from DNA/RNA-hybridization. In some embodiments, the sequencing data is obtained from microarray. In some embodiments, the sequencing data is obtained from DNA/RNA chip. In some embodiments, the sequencing data is obtained from PCR. In some embodiments, the sequencing data is obtained from single nucleotide polymorphism (SNP) genotyping.
- Expression data (e.g., indicating expression levels) for a plurality of genes may be obtained from a biological sample. There is no limit to the number of genes which may be examined. For example, there is no limit to the number of genes for which the expression levels may be examined.
- As a non-limiting example, four or more, five or more, six or more, seven or more, eight or more, nine or more, ten or more, eleven or more, twelve or more, 13 or more, 14 or more, 15 or more, 16 or more, 17 or more, 18 or more, 19 or more, 20 or more, 21 or more, 22 or more, 23 or more, 24 or more, 25 or more, 26 or more, 27 or more, 28 or more, 29 or more, 30 or more, 40 or more, 50 or more, 60 or more, 70 or more, 80 or more, 90 or more, 100 or more, 125 or more, 150 or more, 175 or more, 200 or more, 225 or more, 250 or more, 275 or more, or 300 or more genes may be used for any evaluation described herein. As another set of non-limiting examples, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 125, at least 150, at least 175, at least 200, at least 225, at least 250, at least 275, or at least 300 genes may be used for any evaluation described herein. As a further set of non-limiting examples, up to four, up to five, up to six, up to seven, up to eight, up to nine, up to ten, up to eleven, up to twelve, up to 13, up to 14, up to 15, up to 16, up to 17, up to 18, up to 19, up to 20, up to 21, up to 22, up to 23, up to 24, up to 25, up to 26, up to 27, up to 28, up to 29, up to 30, up to 40, up to 50, up to 60, up to 70, up to 80, up to 90, up to 100, up to 125, up to 150, up to 175, up to 200, up to 225, up to 250, up to 275, or up to 300 genes may be used for any evaluation described herein.
- Any method may be used on a sample from a subject in order to acquire expression data (e.g., indicating expression levels) for the plurality of genes. As a set of non-limiting examples, the expression data may be RNA expression data, DNA expression data, or protein expression data.
- DNA expression data, in some embodiments, refers to a level of DNA in a sample from a subject. The level of DNA in a sample from a subject having cancer may be elevated compared to the level of DNA in a sample from a subject not having cancer, e.g., a gene duplication in a cancer patient's sample. The level of DNA in a sample from a subject having cancer may be reduced compared to the level of DNA in a sample from a subject not having cancer, e.g., a gene deletion in a cancer patient's sample.
- DNA expression data, in some embodiments, refers to data for DNA (or gene) expressed in a sample, for example, sequencing data for a gene that is expressed in a patient's sample. Such data may be useful, in some embodiments, to determine whether the patient has one or more mutations associated with a particular cancer.
- RNA expression data may be acquired using any method known in the art including, but not limited to: whole transcriptome sequencing, total RNA sequencing, mRNA sequencing, targeted RNA sequencing, small RNA sequencing, ribosome profiling, RNA exome capture sequencing, and/or deep RNA sequencing. DNA expression data may be acquired using any method known in the art including any known method of DNA sequencing. For example, DNA sequencing may be used to identify one or more mutations in the DNA of a subject. Any technique used in the art to sequence DNA may be used with the methods and systems described herein. As a set of non-limiting examples, the DNA may be sequenced through single-molecule real-time sequencing, ion torrent sequencing, pyrosequencing, sequencing by synthesis, sequencing by ligation (SOLiD sequencing), nanopore sequencing, or Sanger sequencing (chain termination sequencing). Protein expression data may be acquired using any method known in the art including, but not limited to: N-terminal amino acid analysis, C-terminal amino acid analysis, Edman degradation (including though use of a machine such as a protein sequenator), or mass spectrometry.
- In some embodiments, the expression data comprises whole exome sequencing (WES) data. In some embodiments, the expression data comprises whole genome sequencing (WGS) data. In some embodiments, the expression data comprises next-generation sequencing (NGS) data. In some embodiments, the expression data comprises microarray data.
- Any dataset containing information associated with a biomarker may be used to obtain biomarker information as described herein. In some embodiments, biomarker information may be obtained from one or more databases and/or any other suitable electronic repository of data. Examples of databases include, but are not limited to, CGP (Cancer Genome Project), CPTAC (Clinical Proteomic Tumor Analysis Consortium), ICGC (International Cancer Genome Consortium), and TCGA (The Cancer Genome Atlas). In some embodiments, biomarker information may be obtained from data associated with a clinical trial. In some embodiments, biomarker information may be predicted in association with a clinical trial based on one or more similar drugs (e.g., drugs of a similar class such as PD-1 inhibitors). In some embodiments, biomarker information may be obtained from a hospital database. In some embodiments, biomarker information may be obtained from a commercial sequencing supplier. In some embodiments, biomarker information may be obtained from a subject (e.g., a patient) and/or a subject's (e.g., a patient's) relative, guardian, or caretaker.
- Any of the biological samples described herein can be used for obtaining expression data using conventional assays or those described herein. Expression data, in some embodiments, includes gene expression levels. Gene expression levels may be detected by detecting a product of gene expression such as mRNA and/or protein.
- In some embodiments, gene expression levels are determined by detecting a level of a protein in a sample and/or by detecting a level of activity of a protein in a sample. As used herein, the terms “determining” or “detecting” may include assessing the presence, absence, quantity and/or amount (which can be an effective amount) of a substance within a sample, including the derivation of qualitative or quantitative concentration levels of such substances, or otherwise evaluating the values and/or categorization of such substances in a sample from a subject.
- The level of a protein may be measured using an immunoassay. Examples of immunoassays include any known assay (without limitation), and may include any of the following: immunoblotting assay (e.g., Western blot), immunohistochemical analysis, flow cytometry assay, immunofluorescence assay (IF), enzyme linked immunosorbent assays (ELISAs) (e.g., sandwich ELISAs), radioimmunoassays, electrochemiluminescence-based detection assays, magnetic immunoassays, lateral flow assays, and related techniques. Additional suitable immunoassays for detecting a level of a protein provided herein will be apparent to those of skill in the art.
- Such immunoassays may involve the use of an agent (e.g., an antibody) specific to the target protein. An agent such as an antibody that “specifically binds” to a target protein is a term well understood in the art, and methods to determine such specific binding are also well known in the art. An antibody is said to exhibit “specific binding” if it reacts or associates more frequently, more rapidly, with greater duration and/or with greater affinity with a particular target protein than it does with alternative proteins. It is also understood by reading this definition that, for example, an antibody that specifically binds to a first target peptide may or may not specifically or preferentially bind to a second target peptide. As such, “specific binding” or “preferential binding” does not necessarily require (although it can include) exclusive binding. Generally, but not necessarily, reference to binding means preferential binding. In some examples, an antibody that “specifically binds” to a target peptide or an epitope thereof may not bind to other peptides or other epitopes in the same antigen. In some embodiments, a sample may be contacted, simultaneously or sequentially, with more than one binding agent that binds different proteins (e.g., multiplexed analysis).
- As used herein, the term “antibody” refers to a protein that includes at least one immunoglobulin variable domain or immunoglobulin variable domain sequence. For example, an antibody can include a heavy (H) chain variable region (abbreviated herein as VH), and a light (L) chain variable region (abbreviated herein as VL). In another example, an antibody includes two heavy (H) chain variable regions and two light (L) chain variable regions. The term “antibody” encompasses antigen-binding fragments of antibodies (e.g., single chain antibodies, Fab and sFab fragments, F(ab′)2, Fd fragments, Fv fragments, scFv, and domain antibodies (dAb) fragments (de Wildt et al., Eur J Immunol. 1996; 26(3):629-39.)) as well as complete antibodies. An antibody can have the structural features of IgA, IgG, IgE, IgD, IgM (as well as subtypes thereof). Antibodies may be from any source including, but not limited to, primate (human and non-human primate) and primatized (such as humanized) antibodies.
- In some embodiments, the antibodies as described herein can be conjugated to a detectable label and the binding of the detection reagent to the peptide of interest can be determined based on the intensity of the signal released from the detectable label. Alternatively, a secondary antibody specific to the detection reagent can be used. One or more antibodies may be coupled to a detectable label. Any suitable label known in the art can be used in the assay methods described herein. In some embodiments, a detectable label comprises a fluorophore. As used herein, the term “fluorophore” (also referred to as “fluorescent label” or “fluorescent dye”) refers to moieties that absorb light energy at a defined excitation wavelength and emit light energy at a different wavelength. In some embodiments, a detection moiety is or comprises an enzyme. In some embodiments, an enzyme is one (e.g., β-galactosidase) that produces a colored product from a colorless substrate.
- It will be apparent to those of skill in the art that this disclosure is not limited to immunoassays. Detection assays that are not based on an antibody, such as mass spectrometry, are also useful for the detection and/or quantification of a protein and/or a level of protein as provided herein. Assays that rely on a chromogenic substrate can also be useful for the detection and/or quantification of a protein and/or a level of protein as provided herein.
- Alternatively, the level of nucleic acids encoding a gene in a sample can be measured via a conventional method. In some embodiments, measuring the expression level of nucleic acid encoding the gene comprises measuring mRNA. In some embodiments, the expression level of mRNA encoding a gene can be measured using real-time reverse transcriptase (RT) Q-PCR or a nucleic acid microarray. Methods to detect nucleic acid sequences include, but are not limited to, polymerase chain reaction (PCR), reverse transcriptase-PCR (RT-PCR), in situ PCR, quantitative PCR (Q-PCR), real-time quantitative PCR (RT Q-PCR), in situ hybridization, Southern blot, Northern blot, sequence analysis, microarray analysis, detection of a reporter gene, or other DNA/RNA hybridization platforms.
- In some embodiments, the level of nucleic acids encoding a gene in a sample can be measured via a hybridization assay. In some embodiments, the hybridization assay comprises at least one binding partner. In some embodiments, the hybridization assay comprises at least one oligonucleotide binding partner. In some embodiments, the hybridization assay comprises at least one labeled oligonucleotide binding partner. In some embodiments, the hybridization assay comprises at least one pair of oligonucleotide binding partners. In some embodiments, the hybridization assay comprises at least one pair of labeled oligonucleotide binding partners.
- Any binding agent that specifically binds to a desired nucleic acid or protein may be used in the methods and kits described herein to measure an expression level in a sample. In some embodiments, the binding agent is an antibody or an aptamer that specifically binds to a desired protein. In other embodiments, the binding agent may be one or more oligonucleotides complementary to a nucleic acid or a portion thereof. In some embodiments, a sample may be contacted, simultaneously or sequentially, with more than one binding agent that binds different proteins or different nucleic acids (e.g., multiplexed analysis).
- To measure an expression level of a protein or nucleic acid, a sample can be in contact with a binding agent under suitable conditions. In general, the term “contact” refers to an exposure of the binding agent with the sample or cells collected therefrom for suitable period sufficient for the formation of complexes between the binding agent and the target protein or target nucleic acid in the sample, if any. In some embodiments, the contacting is performed by capillary action in which a sample is moved across a surface of the support membrane.
- In some embodiments, an assay may be performed in a low-throughput platform, including single assay format. In some embodiments, an assay may be performed in a high-throughput platform. Such high-throughput assays may comprise using a binding agent immobilized to a solid support (e.g., one or more chips). Methods for immobilizing a binding agent will depend on factors such as the nature of the binding agent and the material of the solid support and may require particular buffers. Such methods will be evident to one of ordinary skill in the art.
- The various genes recited herein are, in general, named using human gene naming conventions. The various genes, in some embodiments, are described in publically available resources such as published journal articles. The gene names may be correlated with additional information (including sequence information) through use of, for example, the NCBI GenBank® databases available at www<dot>ncbi<dot>nlm<dot>nih<dot>gov; the HUGO (Human Genome Organization) Gene Nomination Committee (HGNC) databases available at www<dot>genenames<dot>org; the DAVID Bioinformatics Resource available at www<dot>david<dot>ncifcrf<dot>gov. It should be appreciated that a gene may encompass all variants of that gene. For organisms or subjects other than human subjects, corresponding specific-specific genes may be used. Synonyms, equivalents, and closely related genes (including genes from other organisms) may be identified using similar databases including the NCBI GenBank® databases described above.
- In some embodiments, gene AXL may be identified as GenBank® Accession number NM_199054.2 or NM_017572.3; gene CCL2 may be identified as GenBank® Accession number NM_002982.3; gene CCL7 may be identified as GenBank® Accession number NM_006273.3; gene CCL8 may be identified as GenBank® Accession number NM_005623.2; gene CDH1 may be identified as GenBank® Accession number NM_004360.4, NM_001317184.1, NM_001317185.1, or NM_001317186.1; gene VEGFC may be identified as GenBank® Accession number NM_005429.4; gene EGFR may be identified as GenBank® Accession number NM_001346941.1, NM_005228.4, NM_001346898.1, NM_001346900.1, NM_001346899.1, NM_001346897.1, NM_201284.1, NM_201283.1 or NM_201282.1; gene ROR2 may be identified as GenBank® Accession number NM_004560.3 or NM_001318204.1; gene PTEN may be identified as GenBank® Accession number NM_001304717.2, NM_000314.6 or NM_001304718.1; gene TAGLN may be identified as GenBank® Accession number NM_001001522.2 or NM_003186.4.
- Normalized biomarker scores derived from a patient and/or a patient's biological sample as described herein may be used for various clinical purposes including, for example, identifying subjects suitable for a particular treatment (e.g., an immunotherapy), and/or predicting likelihood of a patient's response or lack thereof to a particular treatment. Accordingly, described herein are prognostic methods for predicting therapy efficacy, for example, an immunotherapy, based on a patient's biomarker values. Additionally, the systems and methods described herein may be used to predict whether a patient (subject) may or may not have one or more adverse reactions to a particular therapy, based on the patient's biomarker values (e.g., whether a subject is likely to have immune-mediated adverse reactions to checkpoint blockade therapy and/or not have immune-mediated adverse reactions to checkpoint blockade therapy).
- To practice methods for predicting therapeutic efficacy as described herein, a therapy score for a patient may be determined for a particular therapy. As used herein, the term “therapy score” is calculated using multiple normalized biomarker scores for a patient that is indicative of a predicted response of that subject to a therapy. As a set of non-limiting examples, such a “therapy score” may be calculated using multiple normalized biomarker scores in one or more of the following ways: 1) as a sum; 2) as a weighted sum (e.g., in a regression model); 3) using any linear or generalized linear model taking the normalized biomarker scores as inputs and producing, based on the input normalized biomarker scores, an output indicative of a patient's predicted response to a therapy; 4) using any statistical model (e.g., a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a support vector regression model, a Gaussian mixture model, random forest regression, and/or any other suitable type mixture model) taking the normalized biomarker scores as inputs and producing, based on the input biomarker scores, an output indicative of a patient's predicted response to a therapy.
- A therapy score as described herein includes a therapy score calculated using any suitable number of normalized biomarker scores. In some embodiments, the therapy score may be calculated using at least 2 normalized biomarker scores. In some embodiments, the therapy score may be calculated using at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 20, at least 30, at least 40, at least 50, at least 60, at least 70, at least 80, at least 90, or at least 100 normalized biomarker scores.
- In some embodiments, a therapy score is calculated using one or more normalized biomarker values which may be weighted by one or more respective weights as part of the calculation. A biomarker weight may be assigned to any biomarker. For example, an abundant biomarker may be assigned a higher weight for predicting a therapy response. Such weights may be determined, for example, using a machine learning technique. As a non-limiting set of examples, such weights may be determined by training a regression model (e.g., a linear regression model, a generalized linear model, a support vector regression model, a logistic regression model, a random forest regression model, a neural network model, etc.).
- A therapy score for a therapy may be a positive value or a negative value. A positive therapy score, in some embodiments, is indicative of a positive response to a therapy. A negative therapy score, in some embodiments, is indicative of a negative response or no response to a therapy. A therapy score close to zero, in some embodiments, is indicative of little or no measurable response to a therapy.
- A therapy score, in some embodiments, more accurately predicts a patient's response to a therapy when compared, for example, to using a single biomarker. For example, a patient's response to a therapy may be more accurately predicted as a therapy score positively increases in numeric value. In another example, a patient's lack of response to a therapy may be more accurately predicted as a therapy score negatively increases in numeric value.
- The terms “subject” or “patient” may be used interchangeably and refer to a subject who needs the analysis as described herein. In some embodiments, the subject is a human or a non-human mammal (e.g., a non-human primate). In some embodiments, the subject is suspected to have cancer or is at risk for cancer. In some embodiments, the subject has (e.g., is known to have) cancer. Examples of cancer include, without limitation, adrenocortical carcinoma, bladder urothelial carcinoma, breast invasive carcinoma, cervical squamous cell carcinoma, endocervical adenocarcinoma, colon adenocarcinoma, esophageal carcinoma, kidney renal clear cell carcinoma, kidney renal papillary cell carcinoma, liver hepatocellular carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, ovarian serous cystadenocarcinoma, pancreatic adenocarcinoma, prostate adenocarcinoma, rectal adenocarcinoma, skin cutaneous melanoma, stomach adenocarcinoma, thyroid carcinoma, uterine corpus endometrial carcinoma, one or more types of leukemia, and cholangiocarcinoma.
- In some embodiments, the subject is a human patient having one or more symptom of a cancer. For example, the subject may have fatigue, pain, weakness or numbness, loss of bladder or bowl control, cough, blood-tinged saliva, anemia, breast lump or discharge, or a combination thereof. In some embodiments, the subject has a symptom of cancer or has a history of a symptom of cancer. In some embodiments, the subject has more than one symptom of cancer or has a history of more than one symptoms of cancer. In some embodiments, the subject has no symptom of cancer, has no history of a symptom of cancer, or has no history of cancer.
- Such a subject may exhibit one or more symptoms associated with a cancer. Alternatively or in addition, such a subject may have one or more risk factors for cancer, for example, an environmental factor associated with cancer (e.g., geographic location or exposure to a mutagen), a family history of cancer, and/or a genetic predisposition to developing cancer.
- Alternatively, the subject who needs the analysis described herein may be a patient having cancer or suspected of having cancer. Such a subject may currently be having a relapse, or may have suffered from the disease in the past (e.g., may be currently relapse-free), or may have cancer. In some examples, the subject is a human patient who may be on a treatment (i.e., the subject may be receiving treatment) for the disease including, for example, a treatment involving chemotherapy or radiation therapy. In other instances, such a human patient may be free of such a treatment.
- In some embodiments, the systems and methods described herein may be used to assess the effectiveness of a therapy over time. In some embodiments, aspects of the disclosure provide methods and systems for using normalized biomarker scores obtained from samples prior to and subsequent to administration of a candidate therapy to determine the efficacy of that therapy. In some embodiments, such methods may also be used to select a candidate therapy for use with a patient or subject. In certain embodiments, such methods may be used to assess the impact of a candidate therapy, which impact may be quantified by determining an impact score, in accordance with some embodiments described herein.
- For example, some embodiments provide for determining, using a first and second set of normalized biomarker scores for a subject, an impact score for a candidate therapy, wherein the first and second set of normalized biomarker scores are determined using first sequencing data about at least one biological sample of a subject prior to administration of the candidate therapy, and second sequencing data about at least one biological sample of a subject subsequent to administration of the candidate therapy. Such an impact score would be indicative of response (e.g., a positive or negative response) of the subject to administration of the candidate therapy.
- Aspects of the disclosure provide computer implemented methods for determining, using a set of normalized biomarker scores, biomarker scores for a subject indicative of a patient's response or lack thereof to a particular therapy.
- In some embodiments, a software program may provide a user with a visual representation presenting information related to a patient's biomarkers scores (e.g., a biomarker score, and/or a therapy score, and/or an impact score), and predicted efficacy of a therapy. Such a software program may execute in any suitable computing environment including, but not limited to, a cloud-computing environment, a device co-located with a user (e.g., the user's laptop, desktop, smartphone, etc.), one or more devices remote from the user (e.g., one or more servers), etc.
- For example, in some embodiments, the techniques described herein may be implemented in the
illustrative environment 100 shown inFIG. 1A . As shown inFIG. 1A , withinillustrative environment 100, one or more biological samples of apatient 102 may be provided to alaboratory 104.Laboratory 104 may process the biological sample(s) to obtain sequencing data (e.g., transcriptome, exome, and/or genome sequencing data) and provide it, vianetwork 108, to at least onedatabase 106 that stores information aboutpatient 102. -
Network 108 may be a wide area network (e.g., the Internet), a local area network (e.g., a corporate Intranet), and/or any other suitable type of network. Any of the devices shown inFIG. 1A may connect to thenetwork 108 using one or more wired links, one or more wireless links, and/or any suitable combination thereof. - In the illustrated embodiment of
FIG. 1A , the at least onedatabase 106 may store sequencing data for the patient, expression data for the patient, medical history data for the patient, test result data for the patient, and/or any other suitable information about thepatient 102. Examples of stored test result data for the patient include biopsy test results, imaging test results (e.g., MRI results), and blood test results. The information stored in at least onedatabase 106 may be stored in any suitable format and/or using any suitable data structure(s), as aspects of the technology described herein are not limited in this respect. The at least onedatabase 106 may store data in any suitable way (e.g., one or more databases, one or more files). The at least onedatabase 106 may be a single database or multiple databases. - As shown in
FIG. 1A ,illustrative environment 100 includes one or moreexternal databases 116, which may store information for patients other thanpatient 102. For example,external databases 116 may store expression data (of any suitable type) for one or more patients, medical history data for one or more patients, test result data (e.g., imaging results, biopsy results, blood test results) for one or more patients, demographic and/or biographic information for one or more patients, and/or any other suitable type of information. In some embodiments, external database(s) 116 may store information available in one or more publically accessible databases such as TCGA (The Cancer Genome Atlas), one or more databases of clinical trial information, and/or one or more databases maintained by commercial sequencing suppliers. The external database(s) 116 may store such information in any suitable way using any suitable hardware, as aspects of the technology described herein are not limited in this respect. - In some embodiments, the at least one
database 106 and the external database(s) 116 may be the same database, may be part of the same database system, or may be physically co-located, as aspects of the technology described herein are not limited in this respect. - In some embodiments, information stored in
patient information database 106 and/or in external database(s) 116 may be used to perform any of the techniques described herein related to determining a therapy score and/or impact score indicative of a patient's response to a therapy. For example, the information stored in the database(s) 106 and/or 116 may be accessed, vianetwork 108, by software executing on server(s) 110 to perform any one or more of the techniques described herein in connection withFIGS. 2A, 2B, 2C, 2D and 2E . - For example, in some embodiments, server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform
process 200, described with reference toFIG. 2A , for determining therapy scores for multiple therapies based on normalized biomarker scores. - As another example, server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform
process 220, described with reference toFIG. 2B , for determining the effectiveness of a candidate therapy on a patient. - As another example, server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform
process 240, described with reference toFIG. 2C , for determining therapy scores for at least two selected therapies based on normalized biomarker scores for at least three biomarkers for each of the therapies. - As another example, server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform
process 260, described with reference toFIG. 2D , for obtaining first and second therapy scores for first and second therapies. - As yet another example, server(s) 110 may access information stored in database(s) 106 and/or 116 and use this information to perform
process 280, described with reference toFIG. 2E , for identifying a subject as a member of a cohort using normalized biomarker scores. - In some embodiments, server(s) 110 may include one or multiple computing devices. When server(s) 110 include multiple computing devices, the device(s) may be physically co-located (e.g., in a single room) or distributed across multi-physical locations. In some embodiments, server(s) 110 may be part of a cloud computing infrastructure. In some embodiments, one or more server(s) 110 may be co-located in a facility operated by an entity (e.g., a hospital, research institution) with which
doctor 114 is affiliated. In such embodiments, it may be easier to allow server(s) 110 to access private medical data for thepatient 102. - As shown in
FIG. 1A , in some embodiments, the results of the analysis performed by server(s) 110 may be provided todoctor 114 through a computing device 114 (which may be a portable computing device, such as a laptop or smartphone, or a fixed computing device such as a desktop computer). The results may be provided in a written report, an e-mail, a graphical user interface, and/or any other suitable way. It should be appreciated that although in the embodiment ofFIG. 1A , the results are provided to a doctor, in other embodiments, the results of the analysis may be provided topatient 102 or a caretaker ofpatient 102, a healthcare provider such as a nurse, or a person involved with a clinical trial. - In some embodiments, the results may be part of a graphical user interface (GUI) presented to the
doctor 114 via thecomputing device 112. In some embodiments, the GUI may be presented to the user as part of a webpage displayed by a web browser executing on thecomputing device 112. In some embodiments, the GUI may be presented to the user using an application program (different from a web-browser) executing on thecomputing device 112. For example, in some embodiments, thecomputing device 112 may be a mobile device (e.g., a smartphone) and the GUI may be presented to the user via an application program (e.g., “an app”) executing on the mobile device. - The GUI presented on
computing device 112 provides a wide range of oncological data relating to both the patient and the patient's cancer in a new way that is compact and highly informative. Previously, oncological data was obtained from multiple sources of data and at multiple times making the process of obtaining such information costly from both a time and financial perspective. Using the techniques and graphical user interfaces illustrated herein, a user can access the same amount of information at once with less demand on the user and with less demand on the computing resources needed to provide such information. Low demand on the user serves to reduce clinician errors associated with searching various sources of information. Low demand on the computing resources serves to reduce processor power, network bandwidth, and memory needed to provide a wide range of oncological data, which is an improvement in computing technology. -
FIG. 1B shows a block diagram of anillustrative GUI 150 containing information aboutpatient 102.GUI 150 may include separate portions providing different types of information aboutpatient 102.Illustrative GUI 150 includes the following portions:Patient Information Portion 152, Molecular-Functional (MF)Portrait Portion 160, ClinicalTrial Information Portion 162,Immunotherapy Portion 154,Efficacy Predictor Portion 156, and TargetedTherapy Selection Portion 158. -
Patient Information Portion 152 may provide general information about the patient and the patient's cancer. General information about the patient may include such information as the patient's name and date of birth, the patient's insurance provider, and contact information for the patient such as address and phone number. General information about the patient's cancer may include the patient's diagnosis, the patient's history of relapse and/or remission, and information relating to stage of the patient's cancer.Patient Information Portion 152 may also provide information relating to potential treatment options for the patient and/or previously administered treatments. - Molecular-Functional (MF)
Portrait Portion 160 may include a molecular functional tumor portrait (MF profile) which refers to a graphical depiction of a tumor with regard to its molecular and cellular composition, and biological processes that are present within and/or surrounding the tumor. Further aspects relating to a patient's MF profile are provided in International patent application number PCT/US18/37017, entitled “Systems and Methods for Generating, Visualizing and Classifying Molecular Functional Profiles,” filed Jun. 12, 2018, the entire contents of which are incorporated herein by reference. - Clinical
Trial Information Portion 162 may include information relating to a clinical trial for a therapy that may be and/or will be administered to the patient. ClinicalTrial Information Portion 162 may provide information about an ongoing clinical trial or a completed clinical trial. Information that may be provided in ClinicalTrial Information Portion 162 may include information related to a therapy used in the clinical trial such as dosage and dosage regimen, number and diagnosis of patients participating in the clinical trial, and patient outcomes. -
Immunotherapy Portion 154 may include patient specific information as it relates to an immunotherapy.Immunotherapy Portion 154 may provide such information for different immunotherapies, for example, immune checkpoint blockade therapies, anti-cancer vaccine therapies, and T cell therapies. Patient specific information relating to an immunotherapy may include information about the patient such as the patient's biomarkers associated with an immunotherapy and/or information about the patient's cancer such as composition of immune cells in the patient's tumor. -
Efficacy Predictor Portion 156 may include information indicative of the patient's predicted response to an immunotherapy based on patient specific information presented inImmunotherapy Portion 154.Efficacy Predictor Portion 156 may provide predicted efficacy of an immunotherapy determined, in some embodiments, using a patient's biomarkers as described in herein. Additionally or alternatively,Efficacy Predictor Portion 156 may provide predicted efficacy of an immune checkpoint blockade therapy determined using patient specific information such as gene expression data as described in International patent application number PCT/US18/37018, entitled “Systems and Methods for Identifying Responders and Non-Responders to Immune Checkpoint Blockade Therapy,” filed Jun. 12, 2018, the entire contents of which are incorporated herein by reference. - Targeted
Therapy Selection Portion 158 may include patient specific information as it relates to a targeted therapy. TargetedTherapy Selection Portion 158 may provide such information for different targeted therapies, for example, a kinase inhibitor therapy, a chemotherapy, and anti-cancer antibody therapy. Patient specific information relating to an a targeted therapy may include information about the patient such as the patient's biomarkers associated with a targeted therapy and/or information about the patient's cancer such as whether a mutation is present in the patient's tumor. - An illustrative example of the
graphical user interface 150 ofFIG. 1B is shown asgraphical user interface 170 ofFIG. 1C . As shown inFIG. 1C ,Patient Information Portion 172 may provide different information in different panels, for example, Overall Status panel, Disease Characteristics panel, and General Recommendations panel. Overall Status panel, in some embodiments, may provide general information about the patient such as patient name and patient age. Disease Characteristics panel, in some embodiments, may provide information about the patient's cancer such as type of cancer and stage of cancer. General Recommendations panel, in some embodiments, may provide previous treatments and possible treatment options for the patient. - Clinical
Trial Information Portion 182 a provides information relating to a clinical trial for anti-PD1 therapy. ClinicalTrial Information Portion 182 a (as shown in the upper portion) shows a graph providing patient overall response rate (ORR) for anti-PD1 therapy and other therapies such as vaccine or IFNα therapies. A user may select portions of the ClinicalTrial Information Portion 182 a to access information related to patient progression-free survival (PFS) and/or patient overall survival (OS). ClinicalTrial Information Portion 182 a (as shown in the lower portion) provides information relating to different clinical trials that may be presented to a user including a brief description of the clinical trial. - Clinical
Trial Information Portion 182 b provides information relating to a clinical trial for different targeted therapies. ClinicalTrial Information Portion 182 b (as shown in the upper portion) shows a graph providing patient overall response rate (ORR) for different targeted therapies including sunitinib (SU), imatinib (IM), vemurafenib (VER) and dabrafenib (DAB). A user may select portions of the ClinicalTrial Information Portion 182 b to access information related to patient progression-free survival (PFS) and/or patient overall survival (OS). ClinicalTrial Information Portion 182 b (as shown in the lower portion) provides information relating to different clinical trials that may be presented to a user including a brief description of the clinical trial. -
Immunotherapy Portion 174 provides patient specific information associated with an immunotherapy and information indicative of the patient's predicted response to that immunotherapy.Immunotherapy Portion 174 provides such information for anti-PD1 therapy, a therapeutic cancer vaccine, IFNα therapy, IL2 therapy, anti-CTLA4 therapy, and anti-angiogenic therapy. Patient specific information shown inImmunotherapy Portion 174 includes the patient's biomarker information relating to various immunotherapies and the patient's therapy scores calculated from their biomarkers. -
Efficacy Predictor Portion 176 a provides information indicative of the patient's predicted response to anti-PD1 therapy based on patient specific information presented inImmunotherapy Portion 174.Efficacy Predictor Portion 176 b provides information indicative of the patient's predicted response to anti-CTLA4 therapy based on patient specific information presented inImmunotherapy Portion 174. - Targeted
Therapy Selection Portion 178 provides patient specific information associated with a targeted therapy and information indicative of the patient's predicted response to the targeted therapy. TargetedTherapy Selection Portion 178 provides such information for sunitinib (SU), imatinib (IM), vemurafenib (VER), dabrafenib (DAB), trametinib, and pazopanib. Patient specific information shown in TargetedTherapy Selection Portion 178 includes a patient's biomarker information relating to various targeted therapies and the patient's therapy scores calculated from their biomarkers. - An illustrative implementation of a
computer system 1500 that may be used in connection with any of the embodiments of the technology described herein is shown inFIG. 15 . Thecomputer system 1500 may include one or morecomputer hardware processors 1510 and one or more articles of manufacture that comprise non-transitory computer-readable storage media (e.g.,memory 1520 and one or more non-volatile storage devices 1530). The processor(s) 1510 may control writing data to and reading data from thememory 1520 and the non-volatile storage device(s) 1530 in any suitable manner. To perform any of the functionality described herein, the processor(s) 1510 may execute one or more processor-executable instructions stored in one or more non-transitory computer-readable storage media (e.g., the memory 1520), which may serve as non-transitory computer-readable storage media storing processor-executable instructions for execution by the processor(s) 1510. -
FIG. 2A is a flowchart of an illustrative computer-implementedprocess 200 for determining therapy scores for multiple therapies based on normalized biomarker scores, in accordance with some embodiments of the technology described herein. A therapy score provided herein may be indicative of a patient's response to a particular therapy based on the patient's normalized biomarker scores for biomarkers associated with the particular therapy.Process 200 may be performed by any suitable computing device(s). For example,process 200 may be performed by a laptop computer, a desktop computer, one or more servers, in a cloud computing environment, or in any other suitable way. -
Process 200 begins atact 202, where sequencing data for a subject is obtained. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. In some embodiments, obtaining sequencing data comprises obtaining sequencing data from a biological sample obtained from the subject and/or from a database storing such information. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis” and “Obtaining Biomarker Information”. - Next,
process 200 proceeds to act 204, where biomarker information indicating distribution of values for biomarkers associated with multiple therapies is accessed. In some embodiments, for each particular one of multiple therapies, information indicating a respective distribution of values (in a reference population) for each one of one or more biomarkers associated with the particular therapy may be accessed. Such biomarker information may be obtained from one or more databases, in some embodiments. - Next,
process 200 proceeds to act 206, where normalized biomarker scores for the subject are determined using sequencing data obtained atact 202 and the biomarker information obtained atact 204. Normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising any number of biomarkers from any number of reference subjects. In that way, the subject's biomarker score is adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”. - Next,
process 200 proceeds to act 208, where therapy scores for each particular one of the multiple therapies are determined based on normalized biomarker scores for the biomarkers associated with the each particular one therapy. A therapy score may be calculated using multiple normalized biomarker scores as a sum, as a weighted sum, using a linear or generalized linear model, using a statistical model, or combinations thereof. The therapy score may be calculated using any suitable number of normalized biomarker scores, e.g., 2, 10, 50, or 100 normalized biomarker scores. Further aspects relating to determining therapy scores are provided in section “Predicting Therapy Response”. - Therapy scores for any number of therapies may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way. For example, therapy scores and other patient related information may be provided to a user in a GUI as shown in
FIGS. 9-14 . - Systems and methods described herein may be used to assess the effectiveness of a therapy over time. Such systems and methods involve determining an impact score for a candidate therapy indicative of an impact of the candidate therapy on the patient based on the patient's biomarker information obtained prior to and subsequent to administration of the candidate therapy.
-
FIG. 2B is a flowchart of an illustrative computer-implementedprocess 220 for determining an impact score for a candidate therapy using first and second normalized biomarker scores, in accordance with some embodiments of the technology described herein. An impact score provided herein is indicative of a patient's response to a candidate therapy over time based on the patient's normalized biomarker scores obtained before, during and/or after treatment. In some embodiments, a first normalized biomarker score may be obtained before treatment and a second normalized biomarker score may be obtained during and/or after treatment. -
Process 220 begins atact 222, where first sequencing data for a subject prior to administration of a candidate therapy is obtained. Sequencing data for a subject prior to treatment includes any sequencing data obtained for that subject any amount of time prior to treatment. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. Sequencing data for the subject may be obtained minutes, days, months, or years prior to treatment. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”. - Next,
process 220 proceeds to act 224, where second sequencing data for a subject subsequent to administration of a candidate therapy is obtained. Sequencing data for a subject subsequent to treatment includes any sequencing data obtained for that subject any amount of time subsequent to treatment. Sequencing data for the subject may be obtained minutes, days, months, or years subsequent to treatment. The second sequencing data may be a different type of sequencing data than the first sequencing data obtained prior to treatment. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”. - Next,
process 220 proceeds to act 226, where biomarker information indicating a distribution of values for each of multiple biomarkers associated with the candidate therapy is accessed. Accessing biomarker information includes obtaining biomarker information associated with the candidate therapy from a variety of sources including from one or more databases. Biomarker information associated with the candidate therapy may be obtained from a subject prior to administration of a therapy and/or after administration of a therapy. - Next,
process 220 proceeds to act 228, where first and second normalized biomarker scores for the subject are determined using first and second sequencing data and biomarker information. First and second normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising sets of biomarker values for the same biomarkers in multiple reference subjects. In that way, the subject's first and second biomarker score is adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”. - Next,
process 220 proceeds to act 230, where an impact score for the candidate therapy is determined based on first and second normalized biomarker scores. Such impact scores, in some embodiments, may be indicative of efficacy of the candidate therapy. In some embodiments, impact scores may be used to select an additional therapy, stop administration of an ongoing therapy, and/or adjust how an ongoing therapy is being administered for the patient. Further aspects relating to determining impact scores are provided in section “Impact Scores”. - Impact scores for any number and/or any type of candidate therapies may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way. For example, impact scores and other patient related information may be provided to a user in a GUI as shown in
FIGS. 9-14 . - Systems and methods described herein provide a multiple biomarker analysis that provides a more accurate prediction of a patient's response to therapy than that provided by a single biomarker analysis.
-
FIG. 2C is a flowchart of an illustrative computer-implementedprocess 240 for determining therapy scores for at least two selected therapies based on respective normalized biomarker scores for at least three biomarkers, in accordance with some embodiments of the technology described herein. Therapy scores may be determined for selected therapies of any suitable type. For example, therapy scores may be determined for an immune checkpoint blockade therapy (e.g., anti-PD1 therapy) and a kinase inhibitor therapy (e.g., Sunitinib). In another example, therapy scores may be determined for two different immune checkpoint blockade therapies (e.g., anti-PD1 therapy and anti-CTLA4 therapy). Therapy scores may also be determined using any type of three biomarkers. For example, therapy scores may be determined from at least three different genetic biomarkers or therapy scores may be determined from a genetic biomarker, a cellular biomarker, and an expression biomarker. -
Process 240 begins atact 242, where sequencing data for a subject is obtained. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. In some embodiments, obtaining sequencing data comprises obtaining sequencing data from a biological sample obtained from the subject and/or from a database storing such information. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”. - Next,
process 240 proceeds to act 244, where biomarker information indicating distribution of values for the at least three biomarkers associated with the at least two therapies is accessed. For each therapy, information indicating a distribution of values for each of at least three biomarkers associated with each particular therapy may be accessed. Thus, in some embodiments, at least six distributions of values may be accessed (e.g., at least three biomarker value distributions for three biomarkers associated with a first selected therapy and at least three biomarker value distributions for three biomarkers associated with a second selected therapy). Accessing biomarker information may include obtaining biomarker information from a variety of sources including one or more databases. - Next,
process 240 proceeds to act 246, where first and second sets of normalized biomarker scores for the subject are determined using the sequencing data obtained atact 242 and biomarker information obtained atact 244. First and second sets of normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising sets of biomarker values for the same biomarkers in multiple reference subjects. In that way, the subject's first and second sets of biomarker scores are adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers. Since the first set of biomarkers is associated with one therapy and the second set of biomarkers is associated with another therapy, the first and second sets of normalized biomarkers may differ from each other, for example, in number of biomarkers and/or types of biomarkers. For example, the first set of normalized biomarker scores may be associated with a first therapy and the second set of normalized biomarker scores may be associated with a second therapy. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”. Next,process 240 proceeds to act 248, where therapy scores for the at least two therapies are determined based on at least three normalized biomarker scores for each therapy. A therapy score may be calculated using the at least three normalized biomarker scores as a sum, as a weighted sum, using a linear or generalized linear model, using a statistical model, or combinations thereof. The therapy score may be calculated using any suitable number of normalized biomarker scores, e.g., 2, 10, 50, or 100 normalized biomarker scores. Further aspects relating to determining therapy scores are provided in section “Predicting Therapy Response”. - Therapy scores for the at least two therapies and/or biomarker information used for determining therapy scores may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way. For example, therapy scores and other patient related information may be provided to a user in a GUI as shown in
FIGS. 9-14 . - Systems and methods described herein provide for determining more than one therapy score for a particular therapy. For example, a first and a second therapy score may be determined for a first therapy, and a first and second therapy score may be determined for a second therapy.
-
FIG. 2D is a flowchart of an illustrative computer-implementedprocess 260 for determining first and second therapy scores for a first and second therapy, respectively, based on normalized biomarker scores, in accordance with some embodiments of the technology described herein. First and second therapy scores may be determined using different biomarkers or different combinations of biomarkers. For example, a first therapy score is determined based on a patient's genetic biomarkers and a second therapy score is based on the patient's expression biomarkers. In another example, a first therapy score is determined based on a patient's genetic biomarkers and a second therapy score is based on the patient's genetic biomarkers and expression biomarkers. First and second therapy scores may be determined for different therapies and/or different types of therapies. For example, first and second therapy scores may be determined for an immune checkpoint blockade therapy (e.g., anti-PD1 therapy) and a kinase inhibitor therapy (e.g., Sunitinib), respectively. In another example, first and second therapy scores may be determined for two different immune checkpoint blockade therapies (e.g., anti-PD1 therapy and anti-CTLA4 therapy). -
Process 260 begins atact 262, where sequencing data for a subject is obtained. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. In some embodiments, obtaining sequencing data comprises obtaining sequencing data from a biological sample obtained from the subject and/or from a database storing such information. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”. - Next,
process 260 proceeds to act 264, where biomarker information indicating distribution of values for biomarkers associated with at least two therapies. In some embodiments, information indicating a distribution of values is obtained for each of one or more biomarkers associated with a first therapy, and information indicating a distribution of values is obtained for each of one or more biomarkers associated with a second therapy different from the first therapy. Accessing biomarker information may include obtaining biomarker information from a variety of sources including, for example, one or more databases - Next,
process 260 proceeds to act 266, where first and second sets of normalized biomarker scores for the subject are determined using sequencing data obtained atact 262 and biomarker information obtained atact 264. First and second sets of normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising sets of biomarker values for the same biomarkers in multiple reference subjects. In that way, the subject's first and second sets of biomarker scores are adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers. Since the first set of biomarkers is associated with one therapy and the second set of biomarkers is associated with another therapy, the first and second sets of normalized biomarkers may differ from each other, for example, in number of biomarkers and/or types of biomarkers. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”. - Next,
process 260 proceeds to act 268, where first and second therapy scores for the first and second therapies are determined based on normalized biomarker scores for each therapy. A therapy score may be calculated using the normalized biomarker scores as a sum, as a weighted sum, using a linear or generalized linear model, using a statistical model, or combinations thereof. The therapy score may be calculated using any suitable number of normalized biomarker scores, e.g., 2, 10, 50, or 100 normalized biomarker scores. Further aspects relating to determining therapy scores are provided in section “Predicting Therapy Response”. - First and second therapy scores for first and second therapies and/or biomarker information used for determining therapy scores may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way. For example, therapy scores and other patient related information may be provided to a user in a GUI as shown in
FIGS. 9-14 . - Systems and methods described herein may be used to select patients for a clinical trial for a particular therapy based on the patient's predicted response to that therapy determined using the patient's biomarkers as described herein. The systems and methods described herein may be used to identify a patient as a member of a cohort for participation in a clinical trial.
-
FIG. 2E is a flowchart of an illustrative computer-implementedprocess 280 for identifying a subject as a member of a cohort using normalized biomarker scores, in accordance with some embodiments of the technology described herein. A subject may be identified as a member of a cohort for a clinical trial of any type of therapy, for example, a chemotherapy, an immunotherapy, an antibody therapy, and/or any combination thereof. The patient may be identified as a member of a cohort that will be administered the treatment or as a member of a cohort that will be administered a placebo. In some embodiments, the patient may be not be identified as a member of a cohort, and thus may be excluded from participation in a clinical trial. Patients may be excluded from a clinical trial, in some embodiments, if those patients have been predicted to have an adverse reaction to a therapy determined using the patient's biomarkers as described herein and/or the patient's gene expression data as described in International patent application number PCT/US18/37018, entitled “Systems and Methods for Identifying Responders and Non-Responders to Immune Checkpoint Blockade Therapy,” filed Jun. 12, 2018, the entire contents of which are incorporated herein by reference. -
Process 280 begins atact 282, where sequencing data for a subject is obtained. Any type of sequencing data may be obtained, for example, sequencing data from transcriptome, exome, and/or genome sequencing of a patient's tumor biopsy. In some embodiments, obtaining sequencing data comprises obtaining sequencing data from a biological sample obtained from the subject and/or from a database storing such information. Further aspects relating to obtaining sequencing data are provided in section “Sample Analysis”. - Next,
process 280 proceeds to act 284, where biomarker information indicating a distribution of values for each of one or more biomarkers associated with a therapy is accessed. Accessing biomarker information may include obtaining biomarker information from a variety of sources, for example, one or more databases. - Next,
process 280 proceeds to act 286, where normalized biomarker scores for the subject are determined using sequencing data and biomarker information. Normalized biomarker scores for the subject are determined, in some embodiments, using a reference subset of biomarkers comprising sets of biomarker values for the same biomarkers in multiple reference subjects. In that way, the subject's biomarker score is adjusted (e.g., normalized) to a common scale based on a distribution of biomarker values in a reference subset of biomarkers. Further aspects relating to determining normalized biomarker scores are provided in section “From Biomarker Values To Normalized Biomarker Scores”. - Next,
process 280 proceeds to act 288, where a subject is identified as a member of a cohort for participating in a clinical trial using biomarker scores. An identified subject, in some embodiments, may be a subject that is likely to respond positively to the therapy being administered in the clinical trial. Such information may be output to a user, in some embodiments, by displaying the information to the user in a graphical user interface (GUI), including the information in a report, sending an email to the user, and/or in any other suitable way. - In this way, a patient can be identified and selected for participation in a clinical trial based on the patient's biomarker scores. Patients can also be identified for exclusion from the clinical trial, for example, patients predicted not likely to respond positively to the therapy and/or patients predicted to have an adverse reaction to the therapy.
- In some embodiments, a software program may provide a user with a visual representation presenting information related to a patient's biomarker values (e.g., a biomarker score, and/or a therapy score, and/or an impact score), and predicted efficacy or determined efficacy of one or more therapies using a graphical user interface (GUI).
- In response to being launched, the interactive GUI may provide the user of the software program with a visual representation of a patient's biomarker values and/or additional information related to the biomarker.
FIGS. 6A-6C are screenshots presenting such information to a user of the software program. -
FIG. 6A is a screenshot presenting a patient's biomarker information associated with different immunotherapies that may be used to treat the patient. Shading reflects normalized biomarker value in terms of gradient from −1 to 1. Shading intensity increasing as the biomarker value is increased. Shading with lines is assigned to positive biomarker values to distinguish them from negative biomarker values. Numeric “weight” of a biomarker is reflected in the width of the block with larger block width indicating a higher numeric weight. - As shown in
FIG. 6A , a greater number of biomarkers with positive scores were calculated for anti-PD1 therapy indicating a predicted positive therapeutic effect of anti-PD1 therapy for a patient. By contrast, a greater number of biomarkers with negative scores were calculated for anti-VEGF therapy indicating a predicted negative therapeutic effect of anti-VEGF therapy for a patient. Numbers of positive biomarkers and negative biomarkers for a particular therapy may be similar for a patient. In such a case, the therapeutic effects of that therapy for the patient may not be predicted (i.e., may not be accurately predicted). Medium biomarker values for a particular therapy may also indicate that the therapeutic effects of that therapy for the patient may not be predicted (i.e., may not be accurately predicted). -
FIG. 6B is a visual representation illustrating therapy scores calculated using normalized biomarker values shown inFIG. 6A . Negative therapy scores are shown on the left side of the y-axis, and positive therapy scores are shown on the right side of the y-axis. Positive therapy scores are also differentiated from negative therapy scores by shading with lines. - A user may interact with the GUI to obtain additional information about a biomarker.
FIG. 6C is a screenshot presenting information related to each biomarker and patient specific information related to that biomarker. Information presented includes, from left to right, a block representing each biomarker, a description of the biomarker, a graph showing the distribution of biomarker values, and a general description of the biomarker value as “high,” “low,” or “neutral”. The arrow in the graph indicates the patient's biomarker value. In some embodiments a normalized biomarker score may be labeled as a high score when the normalized biomarker score is in the top threshold percent (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%) of a distribution of values. In some embodiments, a normalized biomarker score may be labeled as a low score when the normalized biomarker score is in the bottom threshold percent (e.g., 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%) of a distribution of values. In certain embodiments, a normalized biomarker score may be considered neutral if it is not in the top threshold or the bottom threshold of a distribution of values. -
FIG. 9 is a graphic illustrating different types of screens that may be shown to a user of the software program. Each of the different screens illustrated inFIG. 9 may be used to present different types of information to the user. A screenshot of a control screen of the software program is shown in the middle ofFIG. 9 . The control screen includes portions for presenting information relating to treatment selection, tumor properties, and clinical evidence of treatment efficacy and is described further with respect toFIGS. 10-15 . - A user may interact with the control screen to obtain additional information about, for example, immunotherapy selection, targeted therapy selection, combination therapy design, tumor properties and tumor microenvironment, clinical evidence of targeted therapy efficacy, and clinical evidence of immunotherapy efficacy. The user may select a portion of the control screen (e.g., the immunotherapy portion) to view one or more additional screens presenting information relating to the selected portion. As shown in
FIG. 9 , arrows point from a portion of the control screen that may be selected toward the screens presenting additional information related to the selected portion. - For example, the user may select the immunotherapy selection portion of the control screen to view one or more screens presenting information relating to various immunotherapies, biomarkers associated with an immunotherapy (e.g., genetic biomarkers, cellular biomarkers, and expression biomarkers), immune cell properties of the patient's tumor, and clinical trials (e.g., information from and/or regarding published clinical trials and ongoing clinical trials).
- In another example, the user may select the targeted therapy selection portion of the control screen to view one or more screens presenting information relating to various targeted therapies, biomarkers associated with targeted therapies (e.g., genetic biomarkers, cellular biomarkers, and/or expression biomarkers), properties of the patient's tumor associated with the targeted therapy, and clinical trials (e.g., published clinical trials and ongoing clinical trials).
- In another example, the user may select the molecular-functional portrait (MF profile) portion of the control screen to view one or more screens presenting information relating to the patient's tumor microenvironment. Such information may include information about tumor properties (e.g., proliferation rate), angiogenesis, metastasis, cellular composition, cancer associated fibroblasts, pro-tumor immune environment, and anti-tumor immune environment.
- In yet another example, the user may select the clinical evidence of treatment efficacy portion of the control screen to view one or more screens presenting information relating to a therapy (e.g., an immunotherapy or targeted therapy). Such information may include description of the therapy, therapy efficacy, potential adverse effects, related publications, treatment regimen, and patient survival data.
- In a further example, the user may select a portion of the control screen to view one or more screens associated with an impact score for one or more candidate therapies, wherein the impact score is indicative of response of the subject to administration of the one or more candidate therapies.
- A user of the software program may interact with the GUI to log into the software program. The user may select a stored report to view a screen presenting information relating to the selected report. The user may select the create new report portion to view a screen for creating a new report.
-
FIG. 10 is a screenshot presenting the selected patient's report including information related to the patient's sequencing data, the patient, and the patient's cancer. The therapy biomarkers portion (as shown in the left panel) presents information related to available therapies (e.g., immunotherapies and targeted therapies) and their predicted efficacy in the selected patient. Additional predictions of the efficacy of a therapy in the patient are provided in the machine predictor portion and additional portion (as shown in the left panel). The MF profile portion presents information relating to the molecular characteristics of a tumor including tumor genetics, pro-tumor microenvironment factors, and anti-tumor immune response factors (as shown in the middle panel). The clinical trials portion provides information relating to clinical trials (as shown in the right panel). The monotherapy or combinational therapy portion (as shown in the middle panel) may be selected by the user to interactively design a personalized treatment for a patient. - A user may select various portions of the screen to view additional information. For example, a user may select anti-PD1 in the immunotherapy biomarkers portion of the screen (as shown in the left panel) to view information relating to anti-PD1 treatment including biomarkers associated with anti-PD1 and tumor cell processes associated with anti-PD1 treatment.
-
FIG. 11 is a screenshot presenting information related to anti-PD1 immunotherapy provided in response to selecting anti-PD1 immunotherapy (as shown by highlighting) in the immunotherapy biomarkers portion of the screen (as shown in the left panel). Information relating to biomarkers associated with anti-PD1 immunotherapy is provided in the biomarkers portion (as shown in the right panel). The biomarkers portion presents genetic biomarkers, cellular biomarkers, and expression biomarkers, as well as patient specific information related to those biomarkers. - The user may select any one of the biomarkers presented in the biomarkers markers portion to view additional information relating to that biomarker including general information about the selected biomarker, patient specific information relating to the selected biomarker, information relating to tumor molecular processes associated with the selected biomarker, and treatment related information associated with the selected biomarker.
- In response to selection by a user, the selected biomarker may be visually highlighted. As a set of non-limiting examples, a “visually highlighted” element may be highlighted through a difference in font (e.g., by italicizing, holding, and/or underlining), by surrounding the section with a visual object (e.g., a box), by “popping” the element out (e.g., by increasing the zoom for that element), by changing the color of an element, by shading the element, by incorporation of movement into the element (e.g., by causing the element to move), any combination of the foregoing in a portion or the whole of the element, or in any other suitable way.
FIG. 12 is a screenshot presenting the mutational burden biomarker (as shown by highlighting) was selected by the user. The user may select another portion of the mutational burden biomarker to view a screen presenting information relating to the mutational burden biomarker such as relevant publications. -
FIG. 13 is a screenshot presenting information relating to the mutational burden biomarker (as shown in the middle panel) provided in response to the user selecting the mutational burden biomarker. The information may include a description of the biomarker, how the biomarker was calculated, the patient's particular biomarker value compared to other patients (as shown in a histogram), and information from publications relating to the selected biomarker. - The system allows a user to interactively view biomarker information as it relates to a predicted response to a therapy. Clinical evidence of treatment efficacy for a therapy (e.g., an immunotherapy or a targeted therapy) may be interactively viewed by the user.
-
FIG. 14 is a screenshot presenting clinical trial data relating to anti-PD1 therapy effectivity in patients having stage IV metastatic melanoma (as shown in the right panel) provided in response to the user selecting anti-PD1 immunotherapy (as shown in the left panel). - In certain methods or systems described herein, no recommendation is made regarding administration of a therapy to a subject (e.g., a human). In certain methods described herein, an effective amount of anti-cancer therapy described herein may be administered or recommended for administration to a subject (e.g., a human) in need of the treatment via a suitable route (e.g., intravenous administration).
- The subject to be treated by the methods described herein may be a human patient having, suspected of having, or at risk for a cancer. Examples of a cancer include, but are not limited to, melanoma, lung cancer, brain cancer, breast cancer, colorectal cancer, pancreatic cancer, liver cancer, prostate cancer, skin cancer, kidney cancer, bladder cancer, or prostate cancer. The subject to be treated by the methods described herein may be a mammal (e.g., may be a human). Mammals may include, but are not limited to: farm animals (e.g., livestock), sport animals, laboratory animals, pets, primates, horses, dogs, cats, mice, and rats.
- A subject having a cancer may be identified by routine medical examination, e.g., laboratory tests, biopsy, PET scans, CT scans, or ultrasounds. A subject suspected of having a cancer might show one or more symptoms of the disorder, e.g., unexplained weight loss, fever, fatigue, cough, pain, skin changes, unusual bleeding or discharge, and/or thickening or lumps in parts of the body. A subject at risk for a cancer may be a subject having one or more of the risk factors for that disorder. For example, risk factors associated with cancer include, but are not limited to, (a) viral infection (e.g., herpes virus infection), (b) age, (c) family history, (d) heavy alcohol consumption, (e) obesity, and (f) tobacco use.
- Any anti-cancer therapy or anti-cancer therapeutic agent may be used in conjunction with the methods and systems described herein. In some embodiments, an anti-cancer therapeutic agent is an antibody, an immunotherapy, a molecular targeted therapy, a radiation therapy, a surgical therapy, and/or a chemotherapy.
- Examples of the antibody anti-cancer agents include, but are not limited to, alemtuzumab (Campath), trastuzumab (Herceptin), Ibritumomab tiuxetan (Zevalin), Brentuximab vedotin (Adcetris), Ado-trastuzumab emtansine (Kadcyla), blinatumomab (Blincyto), Bevacizumab (Avastin), Cetuximab (Erbitux), ipilimumab (Yervoy), nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq), avelumab (Bavencio), durvalumab (Imfinzi), and panitumumab (Vectibix).
- Examples of an immunotherapy include, but are not limited to, a PD-1 inhibitor or a PD-L1 inhibitor, a CTLA-4 inhibitor, adoptive cell transfer, therapeutic cancer vaccines, oncolytic virus therapy, T-cell therapy, and immune checkpoint inhibitors.
- Examples of a molecular targeted therapy include, but are not limited to: Uprosertib, Alectinib, Crizotinib, Alisertib, Barasertib, Gilteritinib, Navitoclax, Bosutinib, Dasatinib, Nilotinib, Ponatinib, Imatinib, Dabrafenib, Vemurafenib, Encorafenib, Acalabrutinib, Ibrutinib, Verapamil, Tacrolimus, Abemaciclib, Ribociclib, Palbociclib, Celecoxib, Apricoxib, Selinexor, Plerixafor, Pinometostat, Rociletinib, Pyrotinib, Erlotinib, Gefitinib, Afatinib, Osimertinib, Varlitinib, Icotinib, Lapatinib, Neratinib, Tazemetostat, Tipifarnib, Dovitinib, Lucitanib, Erdafitinib, Crenolanib, Atorvastatin, Onalespib, Enasidenib, Sitagliptin, Ruxolitinib, Tofacitinib, Idasanutlin, Selumetinib. Trametinib, Cobimetinib, Binimetinib, Foretinib, Capmatinib, Tivantinib, Volitinib, Vistusertib, Everolimus, Sirolimus, Torkinib, Temsirolimus, Ridaforolimus, Metformin, Apitolisib, Dactolisib, Brontictuzumab, Omaveloxolone, Dacomitinib, Sapitinib, Poziotinib, Cabozantinib, Regorafenib, Lestaurtinib, Midostaurin, Nintedanib, Pexidartinib, Quizartinib, Sorafenib, Sunitinib, Vandetanib, Entrectinib, Pazopanib, Masitinib, Anlotinib, Brigatinib, Olaparib, Apatinib, Niraparib, Rucaparib, Veliparib, Roflumilast, Idelalisib, Copanlisib, Buparlisib, Taselisib, Pictilisib, Umbralisib, Duvelisib, Alpelisib, Volasertib, Vismodegib, Sonidegib, Saracatinib, Entospletinib, Fostamatinib, Cerdulatinib, Larotrectinib, Auranofin, Axitinib, Cediranib, Lenvatinib, and Alvocidib.
- Examples of radiation therapy include, but are not limited to, ionizing radiation, gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systemic radioactive isotopes, and radiosensitizers.
- Examples of a surgical therapy include, but are not limited to, a curative surgery (e.g., tumor removal surgery), a preventive surgery, a laparoscopic surgery, and a laser surgery.
- Examples of the chemotherapeutic agents include, but are not limited to, Carboplatin or Cisplatin, Docetaxel, Gemcitabine, Nab-Paclitaxel, Paclitaxel, Pemetrexed, and Vinorelbine.
- Additional examples of chemotherapy include, but are not limited to, Platinating agents, such as Carboplatin, Oxaliplatin, Cisplatin, Nedaplatin, Satraplatin, Lobaplatin, Triplatin, Tetranitrate, Picoplatin, Prolindac, Aroplatin and other derivatives; Topoisomerase I inhibitors, such as Camptothecin, Topotecan, irinotecan/SN38, rubitecan, Belotecan, and other derivatives; Topoisomerase H inhibitors, such as Etoposide (VP-16), Daunorubicin, a doxorubicin agent (e.g., doxorubicin, doxorubicin hydrochloride, doxorubicin analogs, or doxorubicin and salts or analogs thereof in liposomes), Mitoxantrone, Aclarubicin, Epirubicin, Idarubicin, Amrubicin, Amsacrine, Pirarubicin, Valrubicin, Zorubicin, Teniposide and other derivatives; Antimetabolites, such as Folic family (Methotrexate, Pemetrexed, Raltitrexed, Aminopterin, and relatives or derivatives thereof); Purine antagonists (Thioguanine, Fludarabine. Cladribine, 6-Mercaptopurine, Pentostatin, clofarabine, and relatives or derivatives thereof) and Pyrimidine antagonists (Cytarabine, Floxuridine, Azacitidine, Tegafur, Carmofur, Capacitabine, Gemcitabine, hydroxyurea, 5-Fluorouracil (5FU), and relatives or derivatives thereof); Alkylating agents, such as Nitrogen mustards (e.g., Cyclophosphamide, Melphalan, Chlorambucil, mechlorethamine, Ifosfamide, mechlorethamine, Trofosfamide, Prednimustine, Bendamustine, Uramustine, Estramustine, and relatives or derivatives thereof); nitrosoureas (e.g., Carmustine, Lomustine, Semustine, Fotemustine, Nimustine, Ranimustine, Streptozocin, and relatives or derivatives thereof); Triazenes (e.g., Dacarbazine, Altretamine, Temozolomide, and relatives or derivatives thereof); Alkyl sulphonates (e.g., Busulfan, Mannosulfan, Treosulfan, and relatives or derivatives thereof); Procarbazine; Mitobronitol, and Aziridines (e.g., Carboquone, Triaziquone, ThioTEPA, triethylenemalamine, and relatives or derivatives thereof); Antibiotics, such as Hydroxyurea, Anthracyclines (e.g., doxorubicin agent, daunorubicin, epirubicin and relatives or derivatives thereof); Anthracenediones (e.g., Mitoxantrone and relatives or derivatives thereof); Streptomyces family antibiotics (e.g., Bleomycin, Mitomycin C, Actinomycin, and Plicamycin); and ultraviolet light.
- “An effective amount” as used herein refers to the amount of each active agent required to confer therapeutic effect on the subject, either alone or in combination with one or more other active agents. Effective amounts vary, as recognized by those skilled in the art, depending on the particular condition being treated, the severity of the condition, the individual patient parameters including age, physical condition, size, gender and weight, the duration of the treatment, the nature of concurrent therapy (if any), the specific route of administration and like factors within the knowledge and expertise of the health practitioner. These factors are well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is generally preferred that a maximum dose of the individual components or combinations thereof be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art, however, that a patient or clinician may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons, or for virtually any other reason(s).
- Empirical considerations, such as the half-life of a therapeutic compound, generally contribute to the determination of the dosage. For example, antibodies that are compatible with the human immune system, such as humanized antibodies or fully human antibodies, may be used to prolong half-life of the antibody and to prevent the antibody being attacked by the host's immune system. Frequency of administration may be determined and adjusted over the course of therapy, and is generally (but not necessarily) based on treatment, and/or suppression, and/or amelioration, and/or delay of a cancer. Alternatively, sustained continuous release formulations of an anti-cancer therapeutic agent may be appropriate. Various formulations and devices for achieving sustained release are known in the art.
- In some embodiments, dosages for an anti-cancer therapeutic agent as described herein may be determined empirically in individuals who have been administered one or more doses of the anti-cancer therapeutic agent. Individuals may be administered incremental dosages of the anti-cancer therapeutic agent. To assess efficacy of an administered anti-cancer therapeutic agent, one or more aspects of a cancer (e.g., tumor formation or tumor growth) may be analyzed.
- Generally, for administration of any of the anti-cancer antibodies described herein, an initial candidate dosage may be about 2 mg/kg. For the purpose of the present disclosure, a typical daily dosage might range from about any of 0.1 μg/kg to 3 μg/kg to 30 μg/kg to 300 μg/kg to 3 mg/kg, to 30 mg/kg to 100 mg/kg or more, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment is sustained until a desired suppression or amelioration of symptoms occurs or until sufficient therapeutic levels are achieved to alleviate a cancer, or one or more symptoms thereof. An exemplary dosing regimen comprises administering an initial dose of about 2 mg/kg, followed by a weekly maintenance dose of about 1 mg/kg of the antibody, or followed by a maintenance dose of about 1 mg/kg every other week. However, other dosage regimens may be useful, depending on the pattern of pharmacokinetic decay that the practitioner (e.g., a medical doctor) wishes to achieve. For example, dosing from one-four times a week is contemplated. In some embodiments, dosing ranging from about 3 μg/mg to about 2 mg/kg (such as about 3 μg/mg, about 10 μg/mg, about 30 μg/mg, about 100 μg/mg, about 300 μg/mg, about 1 mg/kg, and about 2 mg/kg) may be used. In some embodiments, dosing frequency is once every week, every 2 weeks, every 4 weeks, every 5 weeks, every 6 weeks, every 7 weeks, every 8 weeks, every 9 weeks, or every 10 weeks; or once every month, every 2 months, or every 3 months, or longer. The progress of this therapy may be monitored by conventional techniques and assays and/or by monitoring the progress of the disease or cancer as described herein. The dosing regimen (including the therapeutic used) may vary over time.
- When the anti-cancer therapeutic agent is not an antibody, it may be administered at the rate of about 0.1 to 300 mg/kg of the weight of the patient divided into one to three doses, or as disclosed herein. In some embodiments, for an adult patient of normal weight, doses ranging from about 0.3 to 5.00 mg/kg may be administered. The particular dosage regimen, e.g., dose, timing, and/or repetition, will depend on the particular subject and that individual's medical history, as well as the properties of the individual agents (such as the half-life of the agent, and other considerations well known in the art).
- For the purpose of the present disclosure, the appropriate dosage of an anti-cancer therapeutic agent will depend on the specific anti-cancer therapeutic agent(s) (or compositions thereof) employed, the type and severity of cancer, whether the anti-cancer therapeutic agent is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the anti-cancer therapeutic agent, and the discretion of the attending physician. Typically the clinician will administer an anti-cancer therapeutic agent, such as an antibody, until a dosage is reached that achieves the desired result.
- Administration of an anti-cancer therapeutic agent can be continuous or intermittent, depending, for example, upon the recipient's physiological condition, whether the purpose of the administration is therapeutic or prophylactic, and other factors known to skilled practitioners. The administration of an anti-cancer therapeutic agent (e.g., an anti-cancer antibody) may be essentially continuous over a preselected period of time or may be in a series of spaced dose, e.g., either before, during, or after developing cancer.
- As used herein, the term “treating” refers to the application or administration of a composition including one or more active agents to a subject, who has a cancer, a symptom of a cancer, or a predisposition toward a cancer, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve, or affect the cancer or one or more symptoms of the cancer, or the predisposition toward a cancer. In some embodiments, the methods and systems herein may comprise recommendation of a treatment rather than treatment itself. In some embodiments, no recommendation of a treatment will be made. In certain embodiments, one or more potential treatments may be “ranked” or compared according to their predicted efficacy and/or subject or patient outcome. In certain embodiments, one or more potential treatments will not be “ranked” or compared according to their predicted efficacy and/or subject or patient outcome. In some embodiments, information about a therapy (e.g., the therapy score) for a patient will be outputted. In specific embodiments, such information may be outputted to a user (e.g., a doctor or clinician).
- Alleviating a cancer includes delaying the development or progression of the disease, or reducing disease severity (e.g., by at least one parameter). Alleviating the disease does not necessarily require curative results. As used therein, “delaying” the development of a disease (e.g., a cancer) means to defer, hinder, slow, retard, stabilize, and/or postpone progression of the disease. This delay can be of varying lengths of time, depending on the history of the disease and/or individuals being treated. A method that “delays” or alleviates the development or progress of a disease, or delays the onset of one or more complications of the disease, is a method that reduces probability of developing one or more symptoms of the disease in a given time frame and/or reduces extent of the symptoms in a given time frame, when compared to not using the method. Such comparisons are typically based on clinical studies, using a number of subjects sufficient to give a statistically significant result.
- “Development” or “progression” of a disease means initial manifestations and/or ensuing progression of the disease. Development of the disease can be detected and assessed using clinical techniques known in the art. Alternatively or in addition to the clinical techniques known in the art, development of the disease may be detectable and assessed based on biomarkers described herein. However, development also refers to progression that may be undetectable. For purpose of this disclosure, development or progression refers to the biological course of the symptoms. “Development” includes occurrence, recurrence, and onset. As used herein “onset” or “occurrence” of a cancer includes initial onset and/or recurrence.
- In some embodiments, the anti-cancer therapeutic agent (e.g., an antibody) described herein is administered to a subject in need of the treatment at an amount sufficient to reduce cancer (e.g., tumor) growth by at least 10% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or greater). In some embodiments, the anti-cancer therapeutic agent (e.g., an antibody) described herein is administered to a subject in need of the treatment at an amount sufficient to reduce cancer cell number or tumor size by at least 10% (e.g., 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more). In other embodiments, the anti-cancer therapeutic agent is administered in an amount effective in altering cancer type (e.g., from a more severe to a less severe type; or from a worse prognosis to a better prognosis). Alternatively, the anti-cancer therapeutic agent is administered in an amount effective in reducing tumor formation, size, or metastasis.
- Conventional methods, known to those of ordinary skill in the art of medicine, may be used to administer the anti-cancer therapeutic agent to the subject, depending upon the type of disease to be treated or the site of the disease. The anti-cancer therapeutic agent can also be administered via other conventional routes, e.g., administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. In addition, an anti-cancer therapeutic agent may be administered to the subject via injectable depot routes of administration such as using 1-, 3-, or 6-month depot injectable or biodegradable materials and methods.
- Injectable compositions may contain various carriers such as vegetable oils, dimethylactamide, dimethyformamide, ethyl lactate, ethyl carbonate, isopropyl myristate, ethanol, and polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like). For intravenous injection, water soluble anti-cancer therapeutic agents can be administered by the drip method, whereby a pharmaceutical formulation containing the antibody and a physiologically acceptable excipients is infused. Physiologically acceptable excipients may include, for example, 5% dextrose, 0.9% saline, Ringer's solution, and/or other suitable excipients. Intramuscular preparations, e.g., a sterile formulation of a suitable soluble salt form of the anti-cancer therapeutic agent, can be dissolved and administered in a pharmaceutical excipient such as Water-for-Injection, 0.9% saline, and/or 5% glucose solution.
- In one embodiment, an anti-cancer therapeutic agent is administered via site-specific or targeted local delivery techniques. Examples of site-specific or targeted local delivery techniques include various implantable depot sources of the agent or local delivery catheters, such as infusion catheters, an indwelling catheter, or a needle catheter, synthetic grafts, adventitial wraps, shunts and stents or other implantable devices, site specific carriers, direct injection, or direct application. See, e.g., PCT Publication No. WO 00/53211 and U.S. Pat. No. 5,981,568, the contents of each of which are incorporated by reference herein for this purpose.
- Targeted delivery of therapeutic compositions containing an antisense polynucleotide, expression vector, or subgenomic polynucleotides can also be used. Receptor-mediated DNA delivery techniques are described in, for example, Findeis et al., Trends Biotechnol. (1993) 11:202; Chiou et al., Gene Therapeutics: Methods And Applications Of Direct Gene Transfer (J. A. Wolff, ed.) (1994); Wu et al., J. Biol. Chem. (1988) 263:621; Wu et al., J. Biol. Chem. (1994) 269:542; Zenke et al., Proc. Natl. Acad. Sci. USA (1990) 87:3655; Wu et al., J. Biol. Chem. (1991) 266:338. The contents of each of the foregoing are incorporated by reference herein for this purpose.
- Therapeutic compositions containing a polynucleotide may be administered in a range of about 100 ng to about 200 mg of DNA for local administration in a gene therapy protocol. In some embodiments, concentration ranges of about 500 ng to about 50 mg, about 1 μg to about 2 mg, about 5 μg to about 500 μg, and about 20 μg to about 100 μg of DNA or more can also be used during a gene therapy protocol.
- Therapeutic polynucleotides and polypeptides can be delivered using gene delivery vehicles. The gene delivery vehicle can be of viral or non-viral origin (e.g., Jolly, Cancer Gene Therapy (1994) 1:51; Kimura, Human Gene Therapy (1994) 5:845; Connelly, Human Gene Therapy (1995) 1:185; and Kaplitt, Nature Genetics (1994) 6:148). The contents of each of the foregoing are incorporated by reference herein for this purpose. Expression of such coding sequences can be induced using endogenous mammalian or heterologous promoters and/or enhancers. Expression of the coding sequence can be either constitutive or regulated.
- Viral-based vectors for delivery of a desired polynucleotide and expression in a desired cell are well known in the art. Exemplary viral-based vehicles include, but are not limited to, recombinant retroviruses (see, e.g., PCT Publication Nos. WO 90/07936: WO 94/03622; WO 93/25698; WO 93/25234; WO 93/11230; WO 93/10218; WO 91/02805; U.S. Pat. Nos. 5,219,740 and 4,777,127; GB Patent No. 2,200,651; and EP Patent No. 0 345 242), alphavirus-based vectors (e.g., Sindbis virus vectors, Semliki forest virus (ATCC VR-67; ATCC VR-1247), Ross River virus (ATCC VR-373; ATCC VR-1246) and Venezuelan equine encephalitis virus (ATCC VR-923; ATCC VR-1250; ATCC VR 1249; ATCC VR-532)), and adeno-associated virus (AAV) vectors (see, e.g., PCT Publication Nos. WO 94/12649. WO 93/03769; WO 93/19191; WO 94/28938; WO 95/11984 and WO 95/00655). Administration of DNA linked to killed adenovirus as described in Curiel, Hum. Gene Ther. (1992) 3:147 can also be employed. The contents of each of the foregoing are incorporated by reference herein for this purpose.
- Non-viral delivery vehicles and methods can also be employed, including, but not limited to, polycationic condensed DNA linked or unlinked to killed adenovirus alone (see, e.g., Curiel, Hum. Gene Ther. (1992) 3:147); ligand-linked DNA (see, e.g., Wu, J. Biol. Chem. (1989) 264:16985); eukaryotic cell delivery vehicles cells (see, e.g., U.S. Pat. No. 5,814,482; PCT Publication Nos. WO 95/07994: WO 96/17072; WO 95/30763; and WO 97/42338) and nucleic charge neutralization or fusion with cell membranes. Naked DNA can also be employed. Exemplary naked DNA introduction methods are described in PCT Publication No. WO 90/11092 and U.S. Pat. No. 5,580,859. Liposomes that can act as gene delivery vehicles are described in U.S. Pat. No. 5,422,120; PCT Publication Nos. WO 95/13796; WO 94/23697; WO 91/14445; and EP Patent No. 0524968. Additional approaches are described in Philip, Mol. Cell. Biol. (1994) 14:2411, and in Woffendin, Proc. Natl. Acad. Sci. (1994) 91:1581. The contents of each of the foregoing are incorporated by reference herein for this purpose.
- It is also apparent that an expression vector can be used to direct expression of any of the protein-based anti-cancer therapeutic agents (e.g., an anti-cancer antibody). For example, peptide inhibitors that are capable of blocking (from partial to complete blocking) a cancer causing biological activity are known in the art.
- In some embodiments, more than one anti-cancer therapeutic agent, such as an antibody and a small molecule inhibitory compound, may be administered to a subject in need of the treatment. The agents may be of the same type or different types from each other. At least one, at least two, at least three, at least four, or at least five different agents may be co-administered. Generally anti-cancer agents for administration have complementary activities that do not adversely affect each other. Anti-cancer therapeutic agents may also be used in conjunction with other agents that serve to enhance and/or complement the effectiveness of the agents.
- Treatment efficacy can be predicted as described herein for a patient prior to a treatment. Alternatively or in addition to, treatment efficacy can be predicted and/or determined as described herein over the course of treatment (e.g., before, during, and after treatment). See, e.g., Example 4 and Example 5 below.
- Compared to monotherapies, combinations of treatment approaches showed higher efficacy in many studies, but the choice of remedies to be combined and designing the combination therapy regimen remain speculative. Given that the number of possible combinations is now extremely high, there is great need for a tool that would help to select drugs and combinations of remedies based on objective information about a particular patient. Use of biomarkers as described herein for designing or electing a specific combination therapy establishes a scientific basis for choosing the optimal combination of preparations.
- As noted above, also provided herein are methods of treating a cancer or recommending treating a cancer using any combination of anti-cancer therapeutic agents or one or more anti-cancer therapeutic agents and one or more additional therapies (e.g., surgery and/or radiotherapy). The term combination therapy, as used herein, embraces administration of more than one treatment (e.g., an antibody and a small molecule or an antibody and radiotherapy) in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the agents or therapies, in a substantially simultaneous manner.
- Sequential or substantially simultaneous administration of each agent or therapy can be affected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular, subcutaneous routes, and direct absorption through mucous membrane tissues. The agents or therapies can be administered by the same route or by different routes. For example, a first agent (e.g., a small molecule) can be administered orally, and a second agent (e.g., an antibody) can be administered intravenously.
- As used herein, the term “sequential” means, unless otherwise specified, characterized by a regular sequence or order, e.g., if a dosage regimen includes the administration of an antibody and a small molecule, a sequential dosage regimen could include administration of the antibody before, simultaneously, substantially simultaneously, or after administration of the small molecule, but both agents will be administered in a regular sequence or order. The term “separate” means, unless otherwise specified, to keep apart one from the other. The term “simultaneously” means, unless otherwise specified, happening or done at the same time, i.e., the agents of the disclosure are administered at the same time. The term “substantially simultaneously” means that the agents are administered within minutes of each other (e.g., within 10 minutes of each other) and intends to embrace joint administration as well as consecutive administration, but if the administration is consecutive it is separated in time for only a short period (e.g., the time it would take a medical practitioner to administer two agents separately). As used herein, concurrent administration and substantially simultaneous administration are used interchangeably. Sequential administration refers to temporally separated administration of the agents or therapies described herein.
- Combination therapy can also embrace the administration of the anti-cancer therapeutic agent (e.g., an antibody) in further combination with other biologically active ingredients (e.g., a vitamin) and non-drug therapies (e.g., surgery or radiotherapy).
- It should be appreciated that any combination of anti-cancer therapeutic agents may be used in any sequence for treating a cancer. The combinations described herein may be selected on the basis of a number of factors, which include but are not limited to the effectiveness of altering a biomarker, reducing tumor formation or tumor growth, and/or alleviating at least one symptom associated with the cancer, or the effectiveness for mitigating the side effects of another agent of the combination. For example, a combined therapy as provided herein may reduce any of the side effects associated with each individual members of the combination, for example, a side effect associated with an administered anti-cancer agent.
- In order that the systems and methods described herein may be more fully understood, the following examples are set forth. The examples described in this application are offered to illustrate the methods and systems provided herein and are not to be construed in any way as limiting their scope.
- Any number of biomarkers may be used to predict therapy efficacy using a technique provided herein. Biomarkers used herein were obtained from published clinical studies shown in Table 1.
-
TABLE 1 Datasets used for calculating therapy scores. Number of Therapy Dataset Diagnosis biomarkers aPDI therapy Hugo et al. Melanoma 46 aCTLA4 therapy Van Allen et al. Melanoma 17 IFNa therapy TCGA SKCM Melanoma 43 MAGEA-3 vaccine MAGEA3 dataset GSE35640 Melanoma 13 Bevacizumab BEV-bladder-GSE60331 Melanoma 11 Rituximab Based MALY-DE ICGC Follicular lymphoma 18 - In the instant example, biomarkers that split the patient cohorts treated with a particular therapy by a clinical measure (e.g., overall survival (OS), progression-free survival (PFS), objective response rate (ORR), ect.) were used. For example, in patients treated with an anti-PD1 therapy, the PFS for patients having a high number of mutations was 14.5 months and the PFS for patients having a low number of mutations was 3.6 months. Thus, the number of mutations was used as a parameter for predicting therapy efficacy.
- Biomarkers were defined as either positive biomarkers or negative biomarkers based on whether the parameter value of the biomarker corresponds to an increase or decrease in therapy response. Biomarkers were defined as positive biomarkers if their biomarker parameter value correlating to a positive therapy outcome was high. Biomarkers were defined as negative biomarkers if their biomarker parameter value correlating to a negative therapy outcome was high.
- A detailed set of biomarkers for each therapy is presented in Table 2.
-
TABLE 2 Biomarkers obtained from published datasets. Therapy Biomarkers aPDI Affinity of AXL B2M LOF mutation BRAF mutation therapy neontigens BRCA2 mutation Cancer gene panels Cancer gene panels CCL13 (CGPs) FM-CGP (CGPs) HSL-CGP CCL2 CCL7 CCL8 CD8+ cell density in the tumor invasive margin CD8+ cell number CDH1 CVEGFC CX3CL1 expression CXCR2 expression Dendritic cell number EGFR expression Endothelial cells Eosinophil number ESRP1 expression Fibroblasts Granzyme B expression JAKI LOF mutation JAK2 LOF mutation LDH level Lymphocyte number MI macrophage M1/M2 macrophage MDSC % MHC-II expression number ratio MHC-II expression Missmatch-repair MITF expression Mutational Burden (HLA-DRA) deficiency status Pattern of distant PD-L1 expression PD-L1 expression on PTEN loss metastases infiltrating leukocytes Quantity of ROR2 STAT1 expression T reg cell % neoantigen peptides TAGLN TCR clonality TGFbeta level TIL number in tumor TWIST2 VEGF level VEGFA aCTLA4 Absolute CD8+ cell number CXCL11 expression CXCL9 expression therapy lymphocyte count CXCR3 expression Dendritic cell number EOMES + CD8 + cells FOXP3 + cells number number IDO expression LDH expression M1 macrophage M1/M2 macrophage number ratio MDSC % Mutational Burden NY-ESO-1 seropostive PTEN loss T reg cell % TCR clonality TGFbeta level TIL number in tumor VEGF level IL-2 therapy Bone metastasis concomitant regional Leucocytes number LNPEP expression lymphadenopathy C-reactive protein Delta32 CCR5 BCAT2 expression BDNFOS level Polymorphism expression IL-10 (−1082G -> A) CAIX expression LOC130576 CCR5 LOF polymorphism expression mutation ERCC1 (codon 118) IFN-g (+874A -> T) LOC399900 ATP6V0A2 polymorphism polymorphism expression expression Ki-67 expression Alkaline phosphatase ARHGAPI0 CD56+ or CD57+ level expression cells number Liver metastasis CD83+ TIDC cells cDNA FLJ37989 LDH level number expression Fibronectin level HLA-DQB1 GBF1 expression amount of alveolar expression component Albumin level clear cell FOXP3+ cells number HLA-DQA1 bistology expression granular features MAP3K5 expression MDSC number Mediastinum metastasis MEF2A expression MTUS1 expression Neutrophil number NK cell number non clear cell NR1H2 expression NRAS mutations Number of histology metastatic sites papillary features PH-4 expression Platelets Number RABL2B expression RC3H2 expression rs12553173 Sedimentation rate SUPT6H expression TACCI expression TDP1 expression TFPI expression Time from tumor to occurrence of metastases Transferrin level TSH level VCAM1 expression VEGF level Weight loss α-antitrypsin level IFNa CAIX level Delta32 CCR5 Leucocytes count LNPEP expression therapy Polymorphism ERCC1 (codon 118) GBF1 expression Bone metastasis Breslow thickness polymorphism IL-6 expression CCR5 LOF mutation LOC130576 CD4+ cells number level expression Hepatic RIG-1 IL-1ß expression LOC399900 BDNFOS expression level expression expression Interval from initial ARHGAP10 BCAT2 expression CD8+ CD57+ cells diagnosis to expression number treatment Liver metastasis CD83+ TIDC cells cDNA FLJ37989 fis Ki-67 expression number expression HLA-Cw06 allele IL-1α expression HLA-DQB1 ATP6V0A2 level expression expression Alkaline collagen IV level HLA-DQA1 IL-10 (-1082G -> A) phosphatase level expression polymorphism IFN-g (+874A -> T) MAP3K5 expression Mediastinum metastasis MEF2A expression polymorphism MIP-1α expression MIP-1β expression MTAP gene expression MTUS1 expression level level Neutrophil count NR1H2 expression Number of metastatic Osteopontin level sites Performance status PH-4 expression Platelets Number RABL2B expression RC3H2 expression Sedimentation rate Serum calcium level Serum hemoglobin level STAT1 gene SUPT6H expression TACCI expression TDP1 expression expression TFPI expression Time from tumor to TNF-α expression level TRAIL level occurrence of metastases Ulceration of VCAM1 expression VEGF level VEGFR2 level primary Anti-cancer Cancer-Testis CD16+CD56+CD69 CD4 + CD45RO+ cell CD4 + CTLA-4 + T vaccine Antigens' Genes +lymphocytes number cell number therapy expression number CD4 + PD-1 + T cell C-reactive protein ECOG performance EGF level number level score I/II high-grade or III IFN-gamma-induced IgM for Blood Group A IL-6 level T1/2/3a low-grade tumor cell apoptosis trisaccharide level disease intermediate risk Intratumoral versus LDH level Lin-CD14 + HLA-DR-/ lymphocyte number peritumoral T cell lo MDSC level density lymphocytes in M1/M2 macrophage MDSC number Mean Corpuscular PBMC % ratio Hemoglobin Concentration (MCHC) Number of CD27- Patient's age Predictive gene PTEN loss CD45RA+ and signature in MAGE A3 CD27-CD45RA- antigen-specific cancer and immunotherapy CD27 + CD45RA- T- cells Serum amyloid A Serum S100B Syndecan-4 mRNA T reg cell % level concentration expression level TGFbeta level Toll-like receptor 4 WT1 expression gene polymorphism Anti- Acneiform rash Adrenomedullin angiopoietin-2 Bioactive Peptide angiogenic Repeat expression levels Induced Signaling therapy Polymorphism Pathway CD133 expression CDC16 level Child-Pugh class CXCL10 plasma level CXCR1 rs2234671 CXCR2 C785T CXCR2 rs2230054 ECOG Performance G > C T > C Status EGF A-61G EGF rs444903 A > G EGFR expression levels EGFR rs2227983 G > A Endothelin-1 Expression of CD31 Expression of PDGFR- HBV status expression levels beta HGF plasma level History of alcohol ICAM1 T469C IFN-α2 plasma level intake IGF-1 rs6220 A > G IL-12 plasma level IL-16 plasma level IL-2Rα plasma level IL-3 plasma level IL-6 plasma level IL-8 251 T > A IL-8 plasma level Lck and Fyn Liver metastasis M-CSF plasma level mucinous histology tyrosine kinases in initiation of TCR Activation pathway activation NO2-dependent IL Number of resting Number of total PIGF plasma level 12 Pathway circulating circulating endothelial activation in NK endothelial cells cells cells portal vein rs12505758 in rs2286455 rs3130 thrombosis VEGFR2 rs699946 in VEGFA SDF-1α plasma level Sex s VEGFR1 T Cell Receptor T Helper Cell Surface TRAIL plasma level VEGF -1154 A > G Signaling Pathway Molecules expression activation VEGF-1498 C > T VEGF C936T VEGF G-634C VEGF-1154 G/A VEGF-2578 C/A VEGFR1 rs9582036 VEGFR-2 rs2305948 WNK1-rs11064560 C > T Rituximab BCL2 expression BCL6 expression Beclin-1 expression ClqA Gene level Polymorphism Carbohydrate CD163-positive CD20 expression CD37 expression antigen-125 level macrophages level CD5 expression CXCR4 expression Cytotoxic T FcγRIIIa 158H/H level level lymphocyte-associated genotypes Granzyme B expression level Galectin-1 HIPIR mRNA level IL-12 level IL-IRA level expression Ki-67 expression MARCO expression Mast cell number 1 miR-155 expression MYC expression Number of p21 protein expression sLR11 level macrophages SMAD1 expression STAT3 T cells TAM number mRNA level TIM3 expression - To analyze different parameters (e.g., T cell number, MHC protein expression, BRAF mutation, etc.) or parameters for which biomarker “threshold” values could not be clearly interpreted, methods to normalize biomarker values were developed. Normalized biomarker values are herein described in terms of “high,” “medium” and “low,” where mathematically high values correspond to 1 and mathematically low values correspond to −1.
- Biomarkers with digital properties, such as certain mutations (e.g., BRAFV600E), were normalized using a binary system, where presence of a biomarker corresponded to 1, and absence of a biomarker corresponded to 0. Biomarkers associated with protein expression such as those determined from tissue staining experiments, were assigned their corresponding gene expression (e.g., target protein assigned target mRNA expression level).
- Biomarkers associated with cellular composition in the tumor microenvironment were recalculated with bioinformatics cell deconvolution packages based on RNAseq data (e.g., MCPcounter, CIBERSORT).
- Normalized biomarker scores were calculated for a large patient cohort in which patients were diagnosed based on their tumor biopsy. Data was obtained from publicly available databases of human cancer biopsies, and data was normalized for a particular patient using one of the below formulas according to the distribution of biomarker values calculated for the large patient cohort.
- Normalized parameter values in terms of “high” and “low” were calculated based on the Z-score of the parameter value using predefined mathematical functions where the normalized parameter value ranges from −1 to 1 depending on Z-score. Mean and standard deviation were taken from a previously calculated distribution of parameter values for the large patient cohort to which the patient belonged.
- The function was set so that a zero value of the parameter fell in the middle of the distribution, and the highest values were assigned to parameters at the extreme upper end of the distribution.
- Unit step function a):
-
- Where C+cutoff=normalized threshold value representing a “high” parameter value, and C−cutoff=normalized threshold value representing a “low” parameter value.
- Or:
- Flattened unit step function b):
-
- Where a >1=parameter defining the slope of the unit step function. With a >∞ function b) transforms to function a).
- Threshold value C+cutoff(C−cutoff) was equal to 1 (−1), indicating that 15% of patients had a high biomarker value, and 15% of patients had a low biomarker value. Different cut-offs may be used depending on the biomarkers involved in the calculation.
- After normalization, each biomarker was transformed to the same range scale. Thus, a value equal to 1 represents a “high” parameter value, and a value equal to −1 represents a “low” parameter value. Parameter values equal or close to 0 reflect median parameter values according to the distribution. A graphical representation of biomarker value distribution for a large patient cohort is shown in
FIG. 3 . - Biomarkers were assigned weights indicative of their predictive significance based on whether the biomarker was obtained from a large or small patient cohort. Biomarkers obtained from studies using large patient cohorts may have higher predictive significance, and therefore these biomarkers were assigned an initial numeric weight of 3. Biomarkers obtained from studies using small patient cohorts may have lower predictive significance, and therefore these biomarkers were assigned an initial numeric weight of 1.
- Biomarkers were assigned weights indicative of their predictive significance based on the role of the biomarker with respect to a therapy. For example, when analyzing biomarkers for treatment with an anti-PD1 therapy, PDL expression was a significant biomarker that was assigned a higher numeric weight than a less significant biomarker such as gender.
- Biomarker significance in terms of “weight” was defined by expert assessment or clinical studies where the biomarker was identified. Significance or weight was based on clinical measures (e.g., patient outcome) that split two cohorts of patients divided by biomarker value. If the difference among clinical outcomes for a biomarker was large (p-value<0.01), it was assigned a high weight. If the clinical difference for a biomarker was minimal (0.01<p-value<0.05), the biomarker weight was assigned a low weight.
- Alternatively or in addition to the foregoing, biomarker significance was calculated for a biomarker within a set of biomarkers using machine learning algorithms. This approach involved extensive “training” of datasets. A set of biomarkers obtained from literature was tested mathematically to improve weights manually assigned to biomarkers. The algorithm provided a list of significant biomarkers and insignificant biomarkers. Insignificant biomarkers were excluded from the initial set without loss of prediction accuracy.
- Therapy scores were calculated for five patients using a sum of normalized biomarker values multiplied by their “weight”.
Patient 1 andPatient 2 had more positive biomarkers, and thus had higher therapy scores (FIG. 4 ).Patient 4 had similar numbers of positive and negative biomarkers andPatient 5 had biomarkers with neutral values, and thus these patients had therapy scores of zero (FIG. 4 ).Patient 3 had a greater number of negative biomarkers, and thus has a negative therapy score (FIG. 4 ). - Therapy scores for different therapies were calculated for a non-responsive patient (Patient 1) and a responsive patient (Patient 2) with respect to their response to the anti-PD1 therapy Pembrolizumab. Based on the calculated therapy scores,
Patient 1 was likely non-responsive to other treatments including anti-CTLA4 therapy, IL-2 therapy, vaccine therapy, and Bevacizumab (FIG. 5 ). However,Patient 1's therapy score predicted a likely response to IFN-α therapy (FIG. 5 ).Patient 2's therapy scores predicted a likely response to each treatment. These results demonstrated that therapy scores predicted both a response and a non-response to a therapy. - Therapy scores were calculated as described herein for an anti-PD1 therapy dataset and an anti-CTLA4 dataset. Patients treated with an anti-PD1 therapy having higher therapy scores calculated as a sum of positive and negative biomarkers were more likely to respond to therapy, and patients with negative therapy scores were unlikely to respond to therapy (
FIG. 7A ). Similar results were obtained for patients treated with an anti-CTLA4 therapy (FIG. 7B ). - Predictive accuracy was improved by using a prediction cut-off. For example, analysis of the anti-PD1 therapy dataset showed that the prediction rate was 73% when the non-response cut-off was lower than zero and 88% when the non-response cut-off was lower than −1 (
FIG. 7C ). Similarly, the prediction rate was 80% when the response cut-off was higher than zero and improved to 91% when the response cut-off was higher than 1 (FIG. 7C ). Therapy response rate predictions based on certain cut-offs for various therapies are shown in Table 3. -
TABLE 3 Therapy response rate prediction. Non-response Response cut-off Prediction cut-off Prediction Therapy (lower than) rate (higher than) rate aPDI therapy 0 73% 0 80% aCTLA4 therapy −1 77% — — IFNa therapy 0 100% 0 70% MAGEA-3 vaccine −2 94% 0 50% Bevacizumab −1 80% 1 80% Rituximab Based — — 0 100% - Using an anti-PD1 therapy dataset obtained from Hugo et al., the prediction accuracy of therapy scores calculated with biomarker weight optimization were compared to those calculated without biomarker weight optimization. Therapy scores calculated without biomarker weight optimization accurately predicted therapy response for 73% of patients in the study (
FIG. 8A ). Calculating therapy scores with biomarker weight optimization improved the prediction rate to 85%. Biomarker weight optimization included calculating feature importance using random forest regression, in which abundant biomarkers were assigned higher importance for predicting a therapy response (FIG. 8C ). Biomarker weights were recalculated with a logistic regression model to obtain the best prediction of therapy response (FIG. 8D ). - Different combinations of biomarkers were used for calculating therapy scores for different therapies. Normalized biomarker values for each patient treated with anti-PD1 therapy (Table 4-5), aCTLA4 therapy (Table 6-7), IFNα therapy (Table 8), anti-cancer vaccine therapy (Table 9-10), and anti-angiogenic therapy (Table 11) were calculated.
-
TABLE 4 Set of normalized biomarker values for each patient having a negative therapy score treated with aPD1 therapy. ID NO: 87 88 03 29.0 83 95 02 28.0 90 82 96 79 92 84 89 Response PD PD PD PR PD PD PD PR PD PD PD PD CR MIR-BART9 expression 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Cancer gene panels (CGPs) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 FM-CGP Cancer gene panels (CGPs) 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 HSL-CGP BRAF mutation 0.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 0.0 3.0 0.0 3.0 STAT1 expression 0.0 0.0 −0.2 −0.2 −1.6 0.0 −1.0 −1.0 0.0 −0.4 0.0 0.2 0.0 −0.7 0.2 Granzyme B expression −0.2 0.0 0.0 0.0 −0.6 0.0 0.0 0.0 0.0 −0.9 0.0 0.0 0.0 0.0 0.4 Hugogene/AXL −0.5 −0.4 −0.2 −0.2 0.0 0.0 0.0 0.0 −0.5 0.4 0.0 0.0 0.0 0.4 −0.4 Hugogene/ROR2 −0.5 −0.3 −0.5 −0.5 0.0 −0.4 −0.4 −0.4 −0.1 0.0 −0.1 −0.5 0.0 −0.4 0.0 Hugogene/TAGLN −0.2 0.0 0.0 0.0 0.3 −0.5 −0.5 −0.5 −0.2 0.2 −0.4 −0.5 0.0 0.1 −0.5 Hugogene/TWIST2 −0.5 −0.2 0.0 0.0 −0.5 −0.4 −0.1 −0.1 −0.5 0.1 −0.3 −0.5 −0.5 0.0 0.0 Hugogene/CDH1 −2.8 −2.9 −2.4 −2.4 0.3 0.0 0.0 0.0 −2.9 1.6 −1.6 0.5 0.0 −2.5 −2.8 Hugogene/CCL2 0.0 −0.2 −0.4 −0.4 0.4 −0.3 −0.1 −0. −0.5 0.3 0.0 −0.3 −0.3 0.0 −0.5 Hugogene/CCL7 −0.3 0.0 0.0 0.0 0.0 0.0 −0.5 −0.5 −0.5 0.1 −0.5 0.0 −0.5 0.0 −0.5 Hugogene/CCL8 0.0 0.0 0.0 0.0 0.4 −0.3 −0.3 −0.3 −0.5 0.2 −0.5 0.0 −0.4 0.0 −0.4 Hugogene/CCL13 0.1 0.0 0.0 0.0 0.0 0.0 0.1 0.1 −0.5 0.0 0.0 −0.5 −0.5 0.3 −0.1 Hugogene/CVEGFC 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Hugogene/VEGFA −0.9 0.0 0.0 0.0 0.0 0.0 0.1 0.1 −1.0 0.0 0.0 0.0 −0.2 −0.1 −1.0 EGFR expression 0.3 0.0 0.5 0.5 0.0 0.0 0.0 0.0 0.5 −0.2 0.0 0.2 0.0 0.0 0.0 JAK1 LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 −1.5 −1.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 JAK1 LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 B2M LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 LDH level −0.9 0.5 0.3 0.3 0.0 0.0 0.0 0.0 −0.9 0.0 0.8 0.0 −0.6 −0.8 −0.8 Pattern_of_distant_metastases 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Lymphocyte number −1.3 −1.0 0.0 0.0 −2.3 0.0 0.0 0.0 −0.4 −2.4 −0.2 0.0 −0.1 −1.9 0.0 Eosinophil number 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Missmatch-repair deficiency 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 status PD-L1 expression −0.7 −0.6 −0.5 −0.5 −0.3 0.0 0.0 0.0 3.0 0.0 0.0 0.0 0.0 −0.1 0.1 TCR clonality −1.6 −0.6 0.0 0.0 −1.6 1.8 0.0 0.0 1.6 −1.6 0.0 −0.5 3.0 2.4 3.0 Quantity of neoantigen −0.2 −0.6 −0.2 −0.2 −0.2 −0.7 0.0 0.0 0.4 −0.1 −0.1 1.1 0.0 0.0 0.0 peptides Affinity of neontigens 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 CXCR2 expression −0.5 0.0 −0.4 −0.4 −0.5 −0.3 0.0 0.0 0.0 0.0 −0.5 0.0 −0.5 0.0 0.0 ESRP1 expression 1.0 0.0 1.0 1.0 0.3 0.0 0.5 0.5 1.0 −0.1 0.0 0.0 0.5 1.0 1.0 MITF expression 0.8 0.5 0.9 0.9 −0.2 0.0 0.0 0.0 1.0 0.0 0.0 0.0 −0.2 0.0 0.6 Mutational Burden −0.1 −0.4 −0.1 −0.1 −0.1 −0.7 0.0 0.0 0.5 −0.1 −0.1 0.5 0.0 0.0 0.0 BRCA2 mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 3.0 0.0 0.0 0.0 CD8+ cell density in the −2.4 −2.2 0.0 0.0 −2.1 0.0 0.0 0.0 −0.1 −2.3 0.0 0.1 −0.7 −0.1 0.4 tumor invasive margin MHC-II expression −2.6 0.0 0.0 0.0 0.0 0.0 −0.7 −0.7 0.0 −0.7 0.0 0.1 −0.1 −0.2 2.2 EGFR expression 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 CX3CL1 expression 0.3 −0.2 0.0 0.0 0.0 0.0 0.7 0.7 0.5 −1.0 0.7 −0.8 1.0 1.0 0.9 PD-L1 expression on −2.2 −1.7 −1.5 −1.5 −0.8 0.0 0.0 0.0 3.0 −0.1 0.0 0.0 0.0 −0.3 0.1 infiltrating leukocytes VEGF level −2.2 0.0 −0.8 −0.8 0.1 0.0 0.0 0.0 −3.0 0.0 0.0 −0.1 −1.8 0.0 −3.0 TGFbeta level −0.8 0.0 −3.0 −3.0 0.0 −2.9 0.0 0.0 −2.6 0.4 0.0 −1.4 0.0 0.0 −1.1 M1/M2 macrophage ratio −0.3 −0.1 −0.1 −0.1 −0.3 0.0 0.0 0.0 0.0 −0.3 0.0 0.0 −0.3 −0.1 0.0 T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL number in tumor 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 CD8+ cell number 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 M1 macrophage number −2.4 −0.1 −0.2 −0.2 −2.4 0.3 0.0 0.0 0.0 −2.4 0.5 0.0 −2.4 0.0 1.4 Dendritic cell number 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Mutational Burden 0.0 −0.1 0.0 0.0 0.0 −0.2 0.0 0.0 0.5 0.0 0.0 0.5 0.0 0.0 0.0 TCR clonality 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss 0.0 0.1 0.0 0.0 −0.3 0.0 −2.4 −2.4 0.0 0.8 0.0 1.5 1.6 −0.5 −0.2 Fibroblasts −2.9 −2.0 −3.0 −3.0 0.0 −3.0 −2.4 −2.4 −3.0 0.3 −1.5 −2.9 0.0 0.0 −2.9 Endothelial cells −1.6 −0.2 −2.0 −2.0 0.0 −3.0 −0.1 −0.1 −3.0 0.0 −2.7 −3.0 −2.2 0.4 −0.1 Therapy Score −26.2 −9.9 −9.6 −9.6 −9.0 −7.5 −5.6 −5.6 −5.2 −5.0 −3.5 −3.4 −2.4 −2.0 −0.9 Abbreviations; PR—partial response, SD—stable disease, CR—complete response, and CPD—clinical progressive disease. -
TABLE 5 Set of normalized biomarker values for each patient having a positive therapy score treated with aPDI therapy. ID NO: 285 300 297 301 291 293 304 286 305 280 294 281 306 299 298 Response CR PR PD PD PR PR PR CR PR PR PD PR PR CR CR MIR-BART9 expression 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Cancer gene panels 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 (CGPs) FM-CGP Cancer gene panels 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 (CGPs) HSL-CGP BRAF mutation 3.0 0.0 0.0 0.0 0.0 0.0 3.0 3.0 0.0 0.0 0.0 0.0 3.0 0.0 0.0 STAT1 expression −0.1 −2.5 0.0 0.0 0.0 −2.8 0.2 0.0 −1.1 0.3 1.1 0.0 1.1 0.3 2.0 Granzyme B expression −0.1 −0.5 0.0 0.0 0.0 −0.6 0.0 0.0 0.0 −0.3 0.8 0.0 1.0 0.0 0.0 Hugogene/AXL 0.0 0.4 0.0 0.0 0.0 0.4 0.0 0.0 0.3 0.0 0.0 0.0 0.0 0.0 −0.1 Hugogene/ROR2 0.0 0.0 0.2 0.0 0.2 0.0 0.0 0.0 0.2 0.3 0.0 0.2 0.0 0.0 0.0 Hugogene/TAGLN 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 0.4 0.1 0.1 0.0 −0.2 0.3 0.0 Hugogene/TWIST2 −0.2 −0.4 −0.5 0.0 0.0 0.0 0.0 −0.5 0.1 0.0 0.0 0.1 0.0 0.0 −0.3 Hugogene/CDH1 1.3 0.8 −2.9 −0.4 0.2 0.0 1.2 0.0 −2.1 1.4 −0.9 0.9 0.0 2.1 0.4 Hugogene/CCL2 −0.4 −0.1 0.0 0.0 0.0 0.0 0.0 0.0 0.5 0.0 −0.3 0.0 −0.1 0.0 0.0 Hugogene/CCL7 −0.4 −0.5 0.0 0.0 0.0 0.1 0.0 0.0 0.1 0.0 0.0 0.1 0.1 0.1 0.0 Hugogene/CCL8 −0.4 0.2 0.0 −0.4 −0.1 0.3 0.0 −0.3 0.3 0.0 −0.5 0.0 0.0 0.0 0.0 Hugogene/CCL13 −0.5 0.1 0.0 0.0 0.2 0.3 0.0 −0.5 0.3 0.2 −0.2 0.2 0.2 0.3 0.0 Hugogene/CVEGFC 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Hugogene/VEGFA 0.0 0.0 0.9 0.0 0.6 1.0 0.0 0.8 0.9 0.0 0.7 0.4 0.4 0.2 0.2 EGFR expression 0.0 0.5 0.0 0.0 0.0 −0.1 −0.1 0.1 −0.2 0.5 0.0 0.0 0.0 0.0 0.0 JAK1 LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 −1.5 0.0 0.0 0.0 JAKI LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 B2M LOF mutation 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 LDH level 0.3 0.0 1.0 0.1 0.1 1.0 0.0 0.0 −0.3 0.1 0.0 0.0 0.2 −0.4 −0.6 Pattern_of_distant_metastases 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Lymphocyte number −1.3 −0.1 0.0 0.0 0.0 −0.1 −0.1 0.0 0.0 −0.8 2.9 −0.1 3.0 −0.2 0.0 Eosinophil number 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Missmatch-repair 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.5 0.0 1.5 1.5 deficiency status PD-L1 expression 0.0 2.8 0.0 0.0 −0.1 −0.1 0.6 0.0 0.0 0.2 2.4 0.0 2.9 0.6 1.2 TCR clonality 0.0 −1.2 0.0 −0.9 0.1 0.0 −0.1 0.0 0.0 0.0 0.0 0.0 −0.6 0.0 2.6 Quantity of neoantigen 0.0 0.0 −0.5 −0.2 0.0 0.0 −0.1 0.0 0.0 2.4 0.0 3.0 −0.7 2.9 2.9 peptides Affinity of neontigens 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 CXCR2 expression 0.0 −0.5 0.0 0.0 0.0 0.0 0.0 0.0 0.0 −0.5 0.0 −0.5 0.0 0.0 0.0 ESRP1 expression 0.0 −1.0 0.0 0.0 0.1 0.4 −0.8 0.0 0.0 0.1 0.0 0.0 0.8 0.0 0.0 MITF expression 0.0 1.0 0.0 0.0 0.0 0.3 −0.5 0.0 0.0 0.0 −0.1 0.0 0.6 −0.7 −0.5 Mutational Burden 0.0 −0.1 −0.3 −0.2 0.0 0.0 −0.1 0.0 0.0 2.8 0.0 3.0 −0.5 2.7 2.7 BRCA2 mutation 0.0 3.0 0.0 0.0 0.0 3.0 0.0 0.0 0.0 0.0 0.0 3.0 0.0 3.0 3.0 CD8+ cell density in the 0.0 −1.4 0.7 1.0 0.0 0.0 0.0 0.1 0.0 0.0 3.0 −0.1 1.7 −0.1 0.0 tumor invasive margin MHC-II expression 0.0 −0.1 0.0 0.9 0.0 0.0 0.0 0.0 −0.1 0.0 2.5 0.0 2.4 0.0 0.9 EGFR expression 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 CX3CL1 expression 0.2 0.9 0.0 1.0 1.0 0.0 −0.5 −0.2 −0.7 0.0 0.0 0.0 0.0 −0.6 −0.4 PD-L1 expression on 0.0 2.8 0.0 0.0 −0.2 −0.4 0.6 0.0 0.0 0.2 2.4 0.0 2.9 0.6 1.2 infiltrating leukocytes VEGF level 0.0 0.0 2.8 0.0 2.1 3.0 0.0 2.6 2.9 0.0 1.3 2.5 0.0 0.9 0.2 TGFbeta level −0.6 0.1 2.1 0.0 0.2 0.0 0.0 0.0 2.9 0.0 0.7 0.0 −0.1 0.0 0.0 M1/M2 macrophage 0.0 −0.3 0.0 0.5 0.0 0.0 0.9 0.2 0.0 0.0 0.0 0.0 0.0 0.0 0.0 ratio T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL number in tumor 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.9 0.0 0.0 CD8+ cell number 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 M1 macrophage 0.0 −2.4 0.0 3.0 0.0 0.0 3.0 2.8 0.0 0.3 0.0 0.8 −0.1 2.9 3.0 number Dendritic cell number 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 Mutational Burden 0.0 0.0 −0.1 −0.1 0.0 0.0 0.0 0.0 0.0 2.8 0.0 3.0 −0.2 2.7 2.7 TCR clonality 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss 0.2 0.0 −0.2 0.0 −0.7 −2.3 0.0 0.0 0.0 0.0 0.0 0.0 0.6 2.8 2.5 Fibroblasts −0.2 0.0 0.1 0.0 0.6 0.0 0.0 −0.1 2.9 2.2 0.9 2.1 0.0 0.0 0.0 Endothelial cells −0.3 0.0 0.0 0.0 1.2 2.6 −1.2 −0.2 2.9 0.2 0.9 0.0 0.0 0.6 0.0 Therapy Score 0.8 1.4 3.5 4.4 5.3 5.6 6.1 7.9 10.2 12.4 17.6 18.5 20.0 22.6 25.1 Abbreviations; PR—partial response, SD—stable disease, CR—complete response, and CPD—clinical progressive disease. -
TABLE 6 Set of normalized biomarker values for each patient having a negative therapy score treated with aCTLA4 therapy. PD PD PD PD PD PD SD PD PD PD PD PD PD ID NO: 35 38 31 29 16 22 10 28 32 21 34 30 36 CXCL9 −0.9 −0.9 0.0 −0.8 −0.4 −0.9 −0.3 −0.9 −0.9 0.0 −0.9 0.6 0.0 expression CXCL11 −0.8 −0.7 0.0 1.0 −0.5 −0.5 −0.7 −0.2 −0.8 0.0 −0.8 0.0 0.0 expression CXCR3 0.0 −0.4 −0.4 −0.6 0.0 −0.7 0.8 −0.7 −0.7 0.0 −0.5 −0.2 0.0 expression VEGF level −3.0 0.0 −2.8 0.0 0.0 0.0 −2.4 0.0 0.8 −1.2 2.2 −0.2 −1.1 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 FOXP3+ cells 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.1 0.0 0.0 0.0 number Absolute 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 lymphocyte count IDO −2.6 −1.9 −1.2 −2.3 −2.0 −0.7 −0.5 −0.6 −2.6 0.0 −2.5 0.0 −0.1 expression NY-ESO-1 0.0 0.0 0.6 0.0 0.0 0.0 0.0 0.0 1.0 0.0 0.0 0.0 0.0 seropostive EOMES+ CD8+ −0.3 −0.2 −0.2 −0.3 0.0 −0.3 0.0 −0.1 −0.3 0.0 −0.3 0.0 −0.2 cells number LDH −0.2 0.0 0.0 0.0 0.0 0.1 0.2 0.0 0.0 −0.1 0.0 −2.2 0.0 expression VEGF level 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TGFbeta level −0.9 0.0 −0.3 −1.0 −0.8 0.0 −0.8 0.1 0.9 −0.6 0.2 0.0 0.0 M1/M2 0.0 −0.1 −0.1 −0.1 −0.1 0.0 −0.1 −0.2 −0.2 −0.1 −0.2 0.0 −0.1 macrophage ratio T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL number in −2.3 −2.6 −0.3 −2.6 −1.4 −2.9 0.0 −1.9 −2.4 0.0 −2.8 0.0 −0.1 tumor CD8+ cell −0.7 −0.7 −0.3 −0.1 0.0 −0.7 −0.2 −0.7 −0.5 −0.6 0.0 −0.6 −0.7 number M1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 macrophage number Dendritic cell 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 number Mutational 2.1 0.0 −0.1 −0.1 0.0 0.0 0.0 −0.1 0.0 0.0 0.0 0.0 0.0 Burden TCR clonality 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss 1.0 −0.4 0.0 0.0 0.0 0.0 0.5 0.0 0.0 0.0 0.0 0.0 0.0 Therapy Score −8.6 −7.9 −5.1 −6.8 −5.3 −6.6 −3.3 −5.2 −5.7 −2.6 −5.7 −2.6 −2.2 CR SD PD PD PR PR PD SD ID NO: 4 13 26 41 5 6 37 11 CXCL9 −0.9 0.1 0.0 0.0 0.0 0.2 0.0 0.0 expression CXCL11 0.0 0.0 −0.1 0.0 0.0 0.1 −0.3 0.0 expression CXCR3 −0.3 0.0 0.0 0.0 0.0 −0.3 0.0 −0.6 expression VEGF level 0.0 −0.3 0.0 0.0 0.0 0.0 0.3 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 FOXP3+ cells 0.0 0.0 0.1 0.0 0.0 0.0 0.0 0.0 number Absolute 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 lymphocyte count IDO −0.1 0.0 0.0 −0.5 −1.1 0.0 0.0 0.0 expression NY-ESO-1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 seropostive EOMES+ CD8+ 0.0 0.0 0.0 0.0 0.0 0.0 −0.2 0.0 cells number LDH −0.1 −0.8 −0.2 0.0 0.0 −0.6 0.0 0.0 expression VEGF level 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TGFbeta level 0.0 0.0 −0.1 0.1 0.0 0.5 0.2 1.0 M1/M2 −0.1 0.0 −0.1 0.0 0.0 0.2 0.0 0.0 macrophage ratio T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL number in −0.1 0.0 0.0 0.0 −0.5 −0.1 0.0 −0.5 tumor CD8+ cell 0.0 0.0 −0.3 0.0 0.6 0.0 0.0 0.7 number M1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 macrophage number Dendritic cell 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 number Mutational 0.0 0.0 −0.1 −0.1 0.0 0.0 0.0 0.0 Burden TCR clonality 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss 0.0 −0.2 0.0 0.0 0.0 −0.1 0.0 −0.7 Therapy Score −1.6 −1.3 −0.8 −0.6 −0.9 0.0 −0.1 −0.2 Abbreviations; PR—partial response, SD—stable disease, CR—complete response, and CPD—clinical progressive disease. -
TABLE 7 Set of normalized biomarker values for each patient having a positive therapy score treated with aCTLA4 therapy. PD PD SD PD PD CR PR PD PD PD PD PD PD PD SD PR PD SD PR 19 14 24 33 3 8 17 20 25 27 40 18 39 12 7 23 15 9 CXCL9 0.4 0.0 0.3 0.7 0.0 0.0 0.0 0.0 −0.8 0.7 1.0 0.9 0.3 0.9 0.7 0.0 1.0 0.0 expression CXCL11 0.0 −0.3 0.0 0.8 −0.8 0.0 0.7 0.0 0.0 0.1 0.7 0.5 0.0 0.8 0.3 0.0 0.9 1.0 expression CXCR3 0.0 −0.2 0.8 0.9 0.0 0.0 0.9 −0.3 0.0 0.4 1.0 0.1 0.9 1.0 0.8 0.0 0.8 0.0 expression VEGF level 0.1 0.0 0.0 −0.6 −0.4 0.4 0.0 2.1 1.2 0.0 0.0 0.0 1.4 0.0 0.0 1.5 0.0 3.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 FOXP3+ cells 0.0 0.0 1.8 1.7 0.0 0.0 3.0 0.0 0.0 0.0 2.9 1.2 0.0 2.0 1.1 0.0 0.0 0.0 number Absolute 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 lymphocyte count IDO 0.0 0.0 0.0 0.1 0.1 0.0 0.0 0.0 0.0 1.0 1.0 0.0 0.2 0.9 0.9 0.0 1.0 0.9 expression NY-ESO-1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 1.0 1.0 0.0 1.0 0.0 0.0 0.0 0.3 0.0 0.0 seropostive EOMES+ CD8+ 0.0 −0.1 0.0 0.8 0.0 0.0 0.2 0.0 0.0 1.0 1.0 0.0 0.4 1.0 0.6 0.0 1.0 0.0 cells number LOH 0.0 0.0 0.0 0.1 0.0 0.0 0.3 0.0 0.2 −2.8 0.1 0.0 0.0 0.4 −0.3 0.0 −0.2 3.0 expression VEGF level 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TGFbeta level −0.1 0.0 −0.2 −0.9 0.0 0.8 0.0 0.8 0.0 0.5 −0.9 0.0 0.3 −0.2 0.0 0.9 0.9 1.0 M1/M2 0.0 −0.1 0.0 0.0 −0.1 0.0 0.0 −0.2 0.0 0.9 0.4 0.7 0.9 1.0 0.0 0.9 1.0 −0.2 macrophage ratio T reg cell % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 MDSC % 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 TIL number in 0.0 −0.1 1.3 0.4 2.9 0.0 2.9 0.0 0.0 0.0 2.8 0.0 0.7 2.9 1.8 0.0 2.6 0.3 tumor CD8+ cell 0.1 0.1 0.0 0.0 0.0 0.0 −0.3 0.0 1.0 0.9 0.6 0.0 1.0 1.0 0.9 0.0 1.0 0.0 number M1 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 macrophage number Dendritic cell 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 number Mutational 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 −0.1 0.1 0.0 0.0 −0.1 0.2 3.0 3.0 2.8 0.0 Burden TCR clonality 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 PTEN loss −0.3 0.8 0.0 0.0 −0.4 0.0 0.0 −0.7 0.0 0.0 0.0 0.9 0.0 0.0 0.0 0.0 0.2 1.0 Therapy Score 0.2 0.1 3.9 4.0 1.3 1.2 7.7 1.9 2.6 3.7 10.5 5.3 6.1 11.9 9.7 6.8 12.6 10.0 Abbreviations; PR—partial response, SD—stable disease, CR—complete response, and CPD—clinical progressive disease. -
TABLE 8 Set of normalized biomarker values for each patient treated with IFNα therapy. TCGA FR- FS- FW- FS- YG- EB- FW- EB- FS- W3- ER- GN- D3- FR- HR- A7 A1Z FS- D3- A3T A1Z AA3 A6Q A3R A5S A1Z AA1 A19 A4U A8G A44 A2O U8 S A4F0 A2JP V W O Y S H T Q M 5 B A H Response PR SD SD PR SD PR CR CR CR SD CPD CPD CR CR CR CR CR ID: 847 4526 2367 1812 411 1505 1154 382 1124 1643 1617 2101 1857 1156 938 5299 2004 ID NO: 10 16 19 9 13 18 11 4 6 3 17 14 12 7 2 5 8 Delta32 CCR5 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Polymorphism CCR5 LOF 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 mutation IFN-g 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (+874A->T) polymorphism IL-10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (−1082G->A) polymorphism ERCC1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 (codon 118) polymorphism VCAM1 −0.8 −0 −0.8 1 −0 0 −0 −0.5 0 −0 0 0.9 0.6 0 0 0.7 0.5 expression Platelets Number 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Alkaline 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 phosphatase level Sedimentation 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 rate Weight loss 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Time from tumor 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 to occurrence of metastases Number of 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 metastatic sites Bone metastasis 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Liver metastasis 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Mediastinum 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 metastasis GBF1 expression 0.5 −0.5 −0.4 0.5 −0 0.3 −0.2 −0.1 −0.3 −0.4 −0 0.3 0 0 0.5 −0 −0 LNPEP −0.4 0.5 0.5 −0 0.5 −0 0 0 −0 −0.5 −0 −0 0 0 −0.2 0 0 expression MAP3K5 −0.4 0.5 0 −0 −0 −0.2 0 0 −0 −0.5 −0 0 0 0 −0 0.5 0 expression CDNA FLJ37989 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 fis expression RA8L2B 0 0 −0 0.3 −0.3 0.4 −0.5 −0.1 0 −0 −0.3 0.2 −0.1 0 0 0.1 0 expression MEF2A −0 0.5 0.2 −0 0 0 −0 0 0.2 −0.5 0 −0.2 0.1 −0 −0.2 0.3 0 expression LOC399900 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 expression HLA-DQA1 −0.2 −0.4 −0.1 0 0 −0.2 −0 −0.5 −0 −0 −0 0.1 −0 0.4 −0 0.5 0.3 expression TDPI expression 0 0.5 0 −0.5 0.4 0 0 −0 0.4 −0 0 −0.1 0.3 −0 −0.4 −0 0 RC3H2 −0 0.4 0 −0.3 0 −0 0.2 −0 0.3 −0 0.3 −0 0 −0 −0.4 0.1 0.1 expression MTUS1 −0 −0 0 0.5 0 −0 0 −0 0 −0.4 −0 −0.5 0.1 0 −0.2 0 0.4 expression NR1H2 0.1 −0 −0.3 0 0 0.5 0 0 −0 −0.1 0.4 0 −0 −0 0 0 −0 expression SUPT6H 0 −0.5 −0.4 0 −0.1 0.3 −0 −0 0.3 0 −0 0.5 0 -0 0.4 0 −0 expression BCAT2 −0 −0 −0.5 −0 0 0.5 −0 −0 −0 −0 0.1 0.5 0 0 −0 0.4 0 expression LOC130576 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 expression PH-4 expression 0.2 −0.4 0.3 −0 −0.5 0.1 0.3 −0 0.1 0.5 −0 0.5 0.3 −0 −0 −0 −0 ARHGAP10 −0.5 0.1 0.4 0 0 −0.1 −0 −0 0.3 −0.5 0.4 −0 −0.1 −0 0 −0 −0 expression TACC1 −0.5 0.5 −0 0 0.5 −0.2 0.4 0 0.3 0 −0.1 −0.1 −0 −0 −0.1 0 0 expression HLA-DOB1 0.4 −0 −0.4 0 −0 −0 −0 −0.1 −0 −0 −0 0 0.4 0.4 0 0.5 0.5 expression ATP6V0A2 −0.4 0.1 0.2 −0.4 0.5 −0 0.4 0.5 0.2 −0.5 0 0 0.2 −0 −0.3 0 −0 expression TFPI expression −0.3 0 −0 −0 0 −0 −0 −0 0 −0.5 −0 −0.4 −0 −0 0 −0 −0 BDNFOS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 expression HLA-Cw06 allele 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 IL-1α expression −0 −0 −0 −0 −0 −0 −0 2 −0 −0 −0 −0 −0 0.3 −0 −0 −0 level IL-1β expression −0.1 −0.1 −2.1 −0.9 −1.5 −0 −0.1 −0 −0.1 −0.1 0 −1.4 −0 −0 −0 0 0 level IL-6 expression −1.2 0.4 −2.4 −0 −1.5 0.1 −0.7 −1.5 0.1 −1.4 0.9 −0 −0 −0 2.8 −0.1 0.2 level TNF-α expression −1.5 −1.6 −0.8 −1 −0.1 −0 −0 −0 −0.2 −0 0 −0.2 −0.2 0 −0 0 0.1 level MIP-1α −0 −0.2 −2.8 0 −2.1 −0.2 −0.1 −1.4 −0 −0 −0 −2.8 0 0 1.3 2.9 2.9 expression level (CCL3) MIP-1β −2 −0.2 −2.7 0.6 −0 0 −0 −0 0 −0.9 0 −0 2.5 2.3 1 3 3 expression level (CCL4) Performance 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 status Interval from 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 initial diagnosis to treatmen Serum calcium 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 level Serum 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 hemoglobin level Osteopontin level −0 −0 2.9 −2.9 −0 −1.2 0 0 −0 3 0.2 2.9 −1.6 −0 0 −0 0.3 (SPP1) TRAIL level −1.8 0 −0 0 −0 0 −0.1 0.3 0 −1.9 0 −0 1 1.2 0 1.8 2 (TNFSF10) VEGFR2 level 1.5 0 −0 0.4 0 0.2 −0.1 0.4 −0 0 0 −0 0 1.2 0.3 0.1 0.1 (KDR) VEGF level −1 0.1 −0 0.4 −0 0 0 0 −0 1.4 0 0.2 −0 1.4 0.3 0 0 CAIX level −0.3 −0 0.5 0 −0 −1.6 0.6 −0 0.6 0.6 −0 0.6 −0 −0 0 0.2 −0 (CA9) collagen IV level 0 0 −0 0.2 −0.2 1.7 0 0.2 0 1 0 1.9 0 0 −0 0 0.4 (COL4A1; COL4A2; COL4A3; COL4A4; COL4A5) Ulceration of 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 primary Breslow thickness 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 STAT1 gene −0 0.1 2.4 −0 −0 0.4 −0.2 −0 0 −3 0.5 −0 2.7 2.2 −0 2.9 2.9 expression MTAP gene −0 −2.9 1.4 −0 0.4 0 2.2 0.9 2.1 0 0.9 0.2 −2.8 −2.7 −0 −2.5 0 expression Ki-67 expression 0.3 −0 0 1.3 2.3 −0 0 −0 −2.9 2.8 0 3 −0.9 0.6 2.9 0 −0.9 (MK167) Neutrophil count 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Leucocytes count −2.7 −0.8 −0.8 −0 0 0.2 −0 −0.1 0 0 1.8 −0 −0 −0 2.7 1 2.7 CD8+ CD57+ −2.4 −1.5 −2.2 0 0 0 −0 −1 −0 −0 0.3 0 2.5 2.1 0.9 2.9 3 cells number CD4+ cells −2.6 −1.9 −0 0 0.6 −0.8 0 −0 0.3 0 1 2.6 2.7 2.7 0 0.3 3 number CD83+ TIDC cells −1.9 −3 0.8 −2.9 0 0 0 2.9 2.9 1.5 −0.3 −1.7 0.4 0 0 0 −0 number Hepatic RIG-1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 expression (DDX58) Therapy Score −19 −10 −7.2 −3.6 −1 0.2 2.2 2 4.5 −0.4 6.4 7 8.1 12 11 16 21 Abbreviations; PR—partial response, SD—stable disease, CR—complete response, and CPD—clinical progressive disease. -
TABLE 9 Set of normalized biomarker values for each patient having a negative therapy score treated with anti-cancer vaccine therapy. Response NR NR NR NR NR NR NR NR R NR NR NR NR ID NO: 21 33 17 5 26 34 25 22 65 27 3 14 19 TGFbeta level −0.05 2.13 −2.99 0.01 0 −0.17 0 0.36 1.42 −0.03 0.93 0.31 0 M1/M2 macrophage ratio −0 −0 −0 −0 −0 −0 −0 −0 1 −0 1 −0 −0 T reg cell % 0 0 0 0 0 0 0 0 0 0 0 0 0 MDSC number 0 0 0 0 0 0 0 0 0 0 0 0 0 lymphocyte number −2.75 −2.76 −2.44 −1.24 −1.33 −0.07 −2.64 −0.09 −2.34 −2.74 −1.06 −2.64 0.04 ECOG performance 0 0 0 0 0 0 0 0 0 0 0 0 0 score EGF level 0 0 0 0 0 0 0 0 0 0 0 0 0 Cancer-Testis Antigens' 0 0 0 0 0 0 0 0 0 0 0 0 0 Genes expression IFN-gamma-induced 0 0 0 0 0 0 0 0 0 0 0 0 tumor cell apoptosis IL-6 level 0 0 0 0 0 0 0 0 0 0 0 0 0 Mean Corpuscular 0 0 0 0 0 0 0 0 0 0 0 0 0 Hemoglobin Concentration (MCHC) Patient's age 0 0 0 0 0 0 0 0 0 0 0 0 0 Predictive gene signature 0 0 0 0 0 0 0 0 0 0 0 0 0 in MAGE A3 antigen- specific cancer immunotherapy TGFbeta1 level 0 0 0 0 0 0 0 0 0 0 0 0 0 CD16+ CD56+ 0 0 0 0 0 0 0 0 0 0 0 0 0 CD69+ lymphocytes number CD4+ PD-1+ T cell −1.37 0 −0 −0 −2.07 −0.07 0 −0.01 2.37 −1.19 −0.09 0.01 0.01 number_1 C- reactive protein level 0 0 0 0 0 0 0 0 0 0 0 0 0 Intratumoral versus −2.82 −4.02 4.13 −4.13 −4.55 −2.25 −4.02 −3.26 −3.45 −4.06 −3.12 −2.97 −0.12 peritumoral T cell density Serum amyloid A level 0 0 0 0 0 0 0 0 0 0 0 0 0 Toll- like receptor 4gene 0 0 0 0 0 0 0 0 0 0 0 0 0 polymorphism Syndecan-4 mRNA 0 0 0 0 0 0 0 0 0 0 0 0 0 expression level WT1 expression 0 0 0 0 0 0 0 0 0 0 0 0 0 Serum S100B 0 0 0 0 0 0 0 0 0 0 0 0 0 concentration LDH level 0 0 0 0 0 0 0 0 0 0 0 0 0 I/II high-grade or III 0 0 0 0 0 0 0 0 0 0 0 0 0 T1/2/3a low-grade disease_intermediate risk lymphocytes in PBMC % −0.92 −0.92 −0.81 −0.41 −0.44 −0.02 −0.88 −0.03 −0.78 −0.91 −0.35 −0.88 0.01 PTEN loss −0.89 0.94 0 −0.96 1 0.98 0.01 −0 −0.13 1 0.13 0.15 −0.02 CD4+ CD45RO+ cell 0 0 0 0 0 0 0 0 0 0 0 0 0 number Number of CD27- 0 0 0 0 0 0 0 0 0 0 0 0 0 CD45RA+ and CD27- CD45RA− and CD27+ CD45RA− T-cells CD4+ CTLA-4+ T cell 0 0 0 0 0 0 0 0 0 0 0 0 0 number CD4+ PD-1 + T cell 0 0 0 0 0 0 0 0 0 0 0 0 0 number_1 IgM for Blood Group A 0 0 0 0 0 0 0 0 0 0 0 0 0 trisaccharide level Lin-CD14+ HLA-DR-/lo 0 0 0 0 0 0 0 0 0 0 0 0 0 MDSC level B2M −2.93 −2.56 0.08 −0 −0.08 −2.64 0 −2.25 −0.22 0.79 −0.5 −0.04 −2.42 CD86 −2.93 −2.53 −0.39 −2.78 −0.68 −2.91 −1.37 −0 −2.98 −0.43 −2.32 −1.09 −1.27 CXCL10 −2.92 −2.91 −1.62 −2.27 −2.96 −2.92 −0.35 −2.72 −2.48 0.01 −1.97 −0 −0.98 CXCL9 −2.76 −2.93 −2.93 −2.93 −2.91 −2.93 −1.94 −2.9 −1.66 0 −0.03 −0 −0.02 Therapy Score −20.3 −15.6 −15.2 −14.7 −14 −12.0 −11.2 −10.0 −9.25 −7.56 −7.30 −7.15 −4.75 Response NR NR NR NR NR R R NR R R R NR ID NO: 20 28 35 4 15 51 52 2 58 54 66 32 TGFbeta level 1.08 −2.91 0 0 1.57 −0 0.91 0.88 0.19 −0.83 −0.15 1.02 M1/M2 macrophage ratio −0 −0 −0 −0 −0 −0 −0 −0 −0 −0 −0 −0 T reg cell % 0 0 0 0 0 0 0 0 0 0 0 0 MDSC number 0 0 0 0 0 0 0 0 0 0 0 0 lymphocyte number −0.87 −0 −0.01 −0.51 −0.01 0.08 −0.09 −1.48 −0 0 −0.01 −0 ECOG performance 0 0 0 0 0 0 0 0 0 0 0 0 score EGF level 0 0 0 0 0 0 0 0 0 0 0 0 Cancer-Testis Antigens' 0 0 0 0 0 0 0 0 0 0 0 0 Genes expression IFN-gamma-induced 0 0 0 0 0 0 0 0 0 0 0 0 tumor cell apoptosis IL-6 level 0 0 0 0 0 0 0 0 0 0 0 0 Mean Corpuscular 0 0 0 0 0 0 0 0 0 0 0 0 Hemoglobin Concentration (MCHC) Patient's age 0 0 0 0 0 0 0 0 0 0 0 0 Predictive gene signature 0 0 0 0 0 0 0 0 0 0 0 0 in MAGE A3 antigen- specific cancer immunotherapy TGFbeta1 level 0 0 0 0 0 0 0 0 0 0 0 0 CD16+ CD56+ 0 0 0 0 0 0 0 0 0 0 0 0 CD69+ lymphocytes number CD4+ PD-1+ T cell −1.08 −0 0.01 −0 −0.04 0.64 −1.78 0 −0.92 0 −2.52 −1.73 number_1 C- reactive protein level 0 0 0 0 0 0 0 0 0 0 0 0 Intratumoral versus −0.69 −0.01 −0.45 −0.03 −2.17 0.38 −1.34 −0.01 −0 −0.12 −0 0 peritumoral T cell density Serum amyloid A level 0 0 0 0 0 0 0 0 0 0 0 0 Toll- like receptor 4gene 0 0 0 0 0 0 0 0 0 0 0 0 polymorphism Syndecan-4 mRNA 0 0 0 0 0 0 0 0 0 0 0 0 expression level WT1 expression 0 0 0 0 0 0 0 0 0 0 0 0 Serum S100B 0 0 0 0 0 0 0 0 0 0 0 0 concentration LDH level 0 0 0 0 0 0 0 0 0 0 0 0 I/II high-grade or III 0 0 0 0 0 0 0 0 0 0 0 0 T1/2/3a low-grade disease_intermediate risk lymphocytes in PBMC % −0.29 −0 −0 −0.17 −0 0.03 −0.03 −0.49 −0 0 −0 −0 PTEN loss −0.52 0 −0.49 0.69 0.01 −0 0.38 0.86 −0.89 −0.01 −0.95 −0 CD4+ CD45RO+ cell 0 0 0 0 0 0 0 0 0 0 0 0 number Number of CD27- 0 0 0 0 0 0 0 0 0 0 0 0 CD45RA+ and CD27- CD45RA− and CD27+ CD45RA− T-cells CD4+ CTLA-4+ T cell 0 0 0 0 0 0 0 0 0 0 0 0 number CD4+ PD-1 + T cell 0 0 0 0 0 0 0 0 0 0 0 0 number_1 IgM for Blood Group A 0 0 0 0 0 0 0 0 0 0 0 0 trisaccharide leve! Lin-CD14+ HLA-DR-/lo 0 0 0 0 0 0 0 0 0 0 0 0 MDSC level B2M 0 −0 0.04 0 0 −2.94 0.53 −0.93 0.15 0.01 1.33 0.21 CD86 −0.11 −0.6 −2.18 −0.34 0 −0.25 −0 −0.04 0.03 −0 −0 0 CXCL10 −0.12 −0 −0.07 −1.92 −0 0 0 −0.08 0.14 0 1.61 0.03 CXCL9 −1.05 0 −0.08 −0.35 −0.8 0.26 −0.01 −0 0.01 −0 0.23 0.06 Therapy Score −3.65 −3.52 −3.23 −2.63 −1.84 −1.81 −1.43 −1.31 −1.3 −0.95 −0.46 −0.42 Abbreviations; PR—partial response, SD—stable disease, CR—complete response, and CPD—clinical progressive disease. -
TABLE 10 Set of normalized biomarker values for each patient having a positive therapy score treated with anti-cancer vaccine therapy. Response NR NR R R R NR NR R NR NR R ID NO: 29 8 55 63 59 11 12 62 7 18 45 TGFbeta level 0.01 0 0.01 −1.7 0.04 1.42 −1.57 1.25 0.53 −0.27 −0.45 M1/M2 −0 −0 −0 −0 −0 −0 −0 −0 −0 −0 −0 macrophage ratio T reg cell % 0 0 0 0 0 0 0 0 0 0 0 MDSC number 0 0 0 0 0 0 0 0 0 0 0 lymphocyte 0.06 0.29 0.16 −0 0.31 −0 0.93 −0 0.06 0.21 0.12 number ECOG 0 0 0 0 0 0 0 0 0 0 0 performance score EGF level 0 0 0 0 0 0 0 0 0 0 0 Cancer- Testis 0 0 0 0 0 0 0 0 0 0 0 Antigens' Genes expression IFN-gamma- 0 0 0 0 0 0 0 0 0 0 0 induced tumor call apoptosis IL-6 level 0 0 0 0 0 0 0 0 0 0 0 Mean Corpuscular 0 0 0 0 0 0 0 0 0 0 0 Hemoglobin Concentration (MCHC) Patient's age 0 0 0 0 0 0 0 0 0 0 0 Predictive gene 0 0 0 0 0 0 0 0 0 0 0 Signature in MAGE A3 antigen-specific cancer immunotherapy TGFbeta 1 level 0 0 0 0 0 0 0 0 0 0 0 CD16+ CD56+ 0 0 0 0 0 0 0 0 0 0 0 CD69+ lymphocytes number CD4+ PD-1+ T cell 0 −0.06 −0.38 −0.3 0 −0.7 0.02 −0.04 −1.09 2.07 2.77 number_1 C- reactive protein 0 0 0 0 0 0 0 0 0 0 0 level Intratumoral −0 1.84 0 0 0 0.23 0 −0 0.04 0.01 0.15 versus peritumoral T cell density Serum amyloid A 0 0 0 0 0 0 0 0 0 0 0 level Toll- like receptor 40 0 0 0 0 0 0 0 0 0 0 gene polymorphism Syndecan-4 0 0 0 0 0 0 0 0 0 0 0 mRNA expression level WT1 expression 0 0 0 0 0 0 0 0 0 0 0 Serum S100B 0 0 0 0 0 0 0 0 0 0 0 concentration LDH level 0 0 0 0 0 0 0 0 0 0 0 I/II high-grade or III 0 0 0 0 0 0 0 0 0 0 0 T1/2/3a low-grade disease_intermediate risk lymphocytes in 0.02 0.1 0.05 −0 0.1 −0 0.31 −0 0.02 0.07 0.04 PBMC % PTEN loss 0 0 0 −0.57 −0 0.45 −0 0 −0.29 −0.08 0.02 CD4+ CD45RO+ 0 0 0 0 0 0 0 0 0 0 0 cell number Number of CD27- 0 0 0 0 0 0 0 0 0 0 0 CD45RA+ and CD27-CD45RA− and CD27+ CD45RA− T-cells CD4+ PD-1+ T cell 0 0 0 0 0 0 0 0 0 0 0 number_1 IgM for Blood 0 0 0 0 0 0 0 0 0 0 0 Group A trisaccharide level Lin-CD14+ HLA- 0 0 0 0 0 0 0 0 0 0 DR-/lo MDSC level B2M −0.01 −2.93 0.01 0.5 0.31 −1.13 0.02 0 0.69 0.19 0 CD86 −0.02 0.05 0.01 0.72 0 0.44 1.75 0.19 −0 0.04 0.25 CXCL10 −0 0 0.44 1.82 0.01 0.03 −0.25 0 1.13 0.28 −0.01 OXCL9 0.01 1.22 0.53 0.48 0.22 0.41 −0 −0 0.62 0.04 0 Therapy Score 0.05 0.5 0.83 0.95 1 1.17 1.21 1.39 1.7 2.55 2.87 Response NR NR R R NR NR R R R R NR ID NO: 13 31 49 64 23 10 61 16 56 48 24 TGFbeta level −0.12 1.42 −0.04 0.38 −2.69 0 0.22 2 −1.34 −0.23 1.42 M1/M2 −0 −0 −0 −0 −0 −0 −0 −0 −0 −0 −0 macrophage ratio T reg cell % 0 0 0 0 0 0 0 0 0 0 0 MDSC number 0 0 0 0 0 0 0 0 0 0 0 lymphocyte 0.11 0 0.41 0 0.22 2.37 1.58 0 −0 2.99 2.87 number ECOG 0 0 0 0 0 0 0 0 0 0 0 performance score EGF level 0 0 0 0 0 0 0 0 0 0 0 Cancer- Testis 0 0 0 0 0 0 0 0 0 0 0 Antigens' Genes expression IFN-gamma- 0 0 0 0 0 0 0 0 0 0 0 induced tumor call apoptosis IL-6 level 0 0 0 0 0 0 0 0 0 0 0 Mean Corpuscular 0 0 0 0 0 0 0 0 0 0 0 Hemoglobin Concentration (MCHC) Patient's age 0 0 0 0 0 0 0 0 0 0 0 Predictive gene 0 0 0 0 0 0 0 0 0 0 0 Signature in MAGE A3 antigen-specific cancer immunotherapy TGFbeta 1 level 0 0 0 0 0 0 0 0 0 0 0 CD16+ CD56+ 0 0 0 0 0 0 0 0 0 0 0 CD69+ lymphocytes number CD4+ PD-1+ T cell −0.19 1.64 −0 −0.66 −0.01 2.7 −0 0 0 3 −0 number_1 C- reactive protein 0 0 0 0 0 0 0 0 0 0 0 level Intratumoral 0 −0 0.11 0.46 0.86 4.69 2.59 0.75 0.08 4.99 2.83 versus peritumoral T cell density Serum amyloid A 0 0 0 0 0 0 0 0 0 0 0 level Toll- like receptor 40 0 0 0 0 0 0 0 0 0 0 gene polymorphism Syndecan-4 0 0 0 0 0 0 0 0 0 0 0 mRNA expression level WT1 expression 0 0 0 0 0 0 0 0 0 0 0 Serum S100B 0 0 0 0 0 0 0 0 0 0 0 concentration LDH level 0 0 0 0 0 0 0 0 0 0 0 I/II high-grade or III 0 0 0 0 0 0 0 0 0 0 0 T1/2/3a low-grade disease_intermediate risk lymphocytes in 0.04 0 0.14 0 0.07 0.79 0.53 0 −0 1 0.96 PBMC % PTEN loss −0.01 −0.02 0 −0 0.42 −0 0.66 −0.08 0.99 −0.83 −0 CD4+ CD45RO+ 0 0 0 0 0 0 0 0 0 0 0 cell number Number of CD27- 0 0 0 0 0 0 0 0 0 0 0 CD45RA+ and CD27-CD45RA− and CD27+ CD45RA− T-cells CD4+ PD-1+ T cell 0 0 0 0 0 0 0 0 0 0 0 number_1 IgM for Blood 0 0 0 0 0 0 0 0 0 0 0 Group A trisaccharide level Lin-CD14+ HLA- 0 0 0 0 0 0 0 0 0 0 0 DR-/lo MDSC level B2M 0.05 0.02 0.66 1.74 0.83 −3 0.15 1.36 2.61 −2.95 0.02 CD86 0.05 0.76 0 1.15 1.53 −0.03 0 0.41 1.28 0.55 1.36 CXCL10 1.75 0.05 2.09 1.65 2.32 −0.81 0.13 1.63 2.78 −0 0.03 OXCL9 1.5 0 1.52 0.87 2.09 0 0.98 1.85 1.66 0.19 0.04 Therapy Score 3.16 3.87 4.88 5.59 5.64 6.71 6.85 7.92 8.06 8.71 9.52 Response R R NR NR R R R R NR ID NO: 50 46 6 9 47 57 53 60 30 TGFbeta level 0.49 −0 −2.9 −1.05 0.04 0.26 −0 0.08 −0 M1/M2 −0 −0 −0 −0 −0 −0 −0 −0 −0 macrophage ratio T reg cell % 0 0 0 0 0 0 0 0 0 MDSC number 0 0 0 0 0 0 0 0 0 lymphocyte 1.64 0.01 0.12 2.74 0 2.96 2.92 2.63 2.68 number ECOG 0 0 0 0 0 0 0 0 0 performance score EGF level 0 0 0 0 0 0 0 0 0 Cancer- Testis 0 0 0 0 0 0 0 0 0 Antigens' Genes expression IFN-gamma- 0 0 0 0 0 0 0 0 0 induced tumor call apoptosis IL-6 level 0 0 0 0 0 0 0 0 0 Mean Corpuscular 0 0 0 0 0 0 0 0 0 Hemoglobin Concentration (MCHC) Patient's age 0 0 0 0 0 0 0 0 0 Predictive gene 0 0 0 0 0 0 0 0 0 Signature in MAGE A3 antigen-specific cancer immunotherapy TGFbeta 1 level 0 0 0 0 0 0 0 0 0 CD16+ CD56+ 0 0 0 0 0 0 0 0 0 CD69+ lymphocytes number CD4+ PD-1+ T cell −1.39 0 −0 2.99 2.62 2.8 −2.52 0 3 number_1 C- reactive protein 0 0 0 0 0 0 0 0 0 level Intratumoral 0.42 3.69 4.17 4.65 0 4.93 4.89 4.69 4.43 versus peritumoral T cell density Serum amyloid A 0 0 0 0 0 0 0 0 0 level Toll- like receptor 40 0 0 0 0 0 0 0 0 gene polymorphism Syndecan-4 0 0 0 0 0 0 0 0 0 mRNA expression level WT1 expression 0 0 0 0 0 0 0 0 0 Serum S100B 0 0 0 0 0 0 0 0 0 concentration LDH level 0 0 0 0 0 0 0 0 0 I/II high-grade or III 0 0 0 0 0 0 0 0 0 T1/2/3a low-grade disease_intermediate risk lymphocytes in 0.55 0 0.04 0.91 0 0.99 0.97 0.88 0.89 PBMC % PTEN loss 0 −0.41 −0.02 0 −0 −0.65 0 −0.02 −0.36 CD4+ CD45RO+ 0 0 0 0 0 0 0 0 0 cell number Number of CD27- 0 0 0 0 0 0 0 0 0 CD45RA+ and CD27-CD45RA− and CD27+ CD45RA− T-cells CD4+ PD-1+ T cell 0 0 0 0 0 0 0 0 0 number_1 IgM for Blood 0 0 0 0 0 0 0 0 0 Group A trisaccharide level Lin-CD14+ HLA- 0 0 0 0 0 0 0 0 0 DR-/lo MDSC level B2M 2.61 1.78 2 −2.38 2.12 0 1.29 2.27 0.02 CD86 2.04 2.27 2.53 2.7 2.35 1.79 2.84 2.2 2.89 CXCL10 2.26 2.38 2.57 0.16 2.51 −0 2.08 2.24 2.76 OXCL9 2.02 1.04 2.26 1.25 2.37 0.02 2.27 2.02 2.18 Therapy Score 10.6 10.8 10.8 12 12 13.1 14.7 17 18.5 Abbreviations; PR—partial response, SD—stable disease, CR—complete response, and CPD—clinical progressive disease. -
TABLE 11 Set of normalized biomarker values for each patient treated with anti-angiogenic therapy. Patient ID GSM14718 39 86 53 58 75 42 Response: NR NR NR NR R R Timepoint: PT PT PT PT PT PT Number of resting 0.000162 1.97328 0.00283 1.3E−06 −0.67291 −0.97508 circulating endothelial cells Number of total 0 0 0 0 0 0 circulating endothelial cells Expression of −2.97683 −0.00033 −0.00618 −0.69032 0.001726 0.000607 PDGFR-beta Expression of 0 0.570456 0.000747 1.482181 0 2.460252 CD31 CDC16 level 9.4E−07 −0.11814 −1.60473 1.244301 −0.09602 3.4E−05 Lck and Fyn −0.96874 0.730858 −0.38819 −0.14019 1.06E−06 −0.18482 tyrosine kinases in initiation of TCR Activation pathway activation T Cell Receptor 0 0 0 0 0 0 Signaling Pathway activation T Helper Cell 0 0 0 0 0 0 Surface Molecules expression NO2-dependent 0 0 0 0 0 0 IL. 12 Pathway activation in NK cells Bioactive Peptide 0 0 0 0 0 0 Induced Signaling Pathway sVEGFR1 −2.99459 −0.2038 1.932855 0.000431 −0.01157 −0.33766 CD133 0 0 0 0 0 0 expression rs2286455 0 0 0 0 0 0 rs3130 0 0 0 0 0 0 IL-6 plasma level 0 0 0 0 IL-8 plasma level 0 0 0 0 0 0 Child- Pugh class 0 0 0 0 0 0 HBV status 0 0 0 0 0 0 portal vein 0 0 0 0 0 0 thrombosis Sex 0 0 0 0 0 0 History of alcohol 0 0 0 0 0 0 intake Acneiform rash 0 0 0 0 0 angiopoietin-2 −8.4E−11 −0.81987 −0.2002 −2.53227 0.001005 −2.10171 expression levels EGFR expression −0.98928 −0.34509 1.07E−06 −0.00033 0.045048 0.098944 levels Endothelin-1 0.754617 −4.3E−08 −0.02217 −0.73196 0.198087 −0.00242 expression levels angiopoietin-2 0 0 0 0 0 0 expression levels IL-12 plasma 0 0 0 0 0 0 level HGF plasma level 0 0 0 0 0 0 IL-16 plasma 0 0 0 0 0 0 level CXCL10 plasma 0 0 0 0 0 0 level SDF-1α plasma 0 0 0 0 0 0 level IL- 2Rα plasma 0 0 0 0 0 0 level IL-3 plasma level 0 0 0 0 0 0 IFN-α2 plasma 0 0 0 0 0 0 level TRAIL plasma 0 0 0 0 0 0 level M-CSF plasma 0 0 0 0 0 0 level PIGF plasma 0 0 0 0 0 0 level mucinous 0 0 0 0 0 0 histology VEGF -1498 C> T 0 0 0 0 0 0 Liver metastasis 0 0 0 0 0 0 ECOG Performance 0 0 0 0 0 0 Status VEGF -1154 A> G 0 0 0 0 0 0 VEGF G-634C 0 0 0 0 0 0 ICAM1 T469C 0 0 0 0 0 0 WNK1- 0 0 0 0 0 0 rs11064560 EGF A-61G 0 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 0 VEGF-1154 G/ A 0 0 0 0 0 0 VEGF-2578 C/ A 0 0 0 0 rs699346 in 0 0 0 0 0 0 VEGFA rs 12505758 in 0 0 0 0 0 0 VEGFR2 VEGFR1 0 0 0 0 0 0 rs9582036 EGF rs444903 0 0 0 0 0 0 A>G IGF-1 rs6220 0 0 0 0 0 0 A>G CXCR1 0 0 0 0 0 0 rs2234671 G>C CXCR2 0 0 0 0 0 0 rs2230054 T>C EGFR rs2227983 0 0 0 0 0 0 G>A VEGFR-2 0 0 0 0 0 0 rs2305948 C>T IL-8 251 T>A 0 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 0 VEGF C936T 0 0 0 0 0 0 Adrenomedullin 0 0 0 0 0 Repeat 0 Polymorphism VEGFA 0 0 0 0 0 0 ICAM1 −0.27451 0.000147 −1.3524 −1.2E−09 −0.35542 0.304107 Therapy Score −7.44919 −2.15904 −1.64309 −1.36816 −0.89005 −0.73775 Patient ID GSM14718 82 71 47 50 64 67 Response: NR R R NR NR NR Timepoint: PT PT PT PT PT PT Number of resting −0.68776 −0.00018 0.533442 −0.00749 0.573339 −1.67907 circulating endothelial cells Number of total 0 0 0 0 0 0 circulating endothelial cells Expression of 0.004197 −1.29847 −0.18186 −0.38181 0.00909 −0.26866 PDGFR-beta Expression of 1.408502 0.000326 0 3.95E−05 0 3.95E−05 CD31 CDC16 level −1.0432 −0.02895 −1.6E−07 −0.04842 −0.0615 1.26E−06 Lck and Fyn 1.58E−05 0.00172 0.002242 1.33E−09 −3.5E−06 0.097905 tyrosine kinases in initiation of TCR Activation 0 0 0 0 0 0 pathway activation T Cell Receptor 0 0 0 0 0 0 Signaling Pathway activation T Helper Cell 0 0 0 0 0 0 Surface Molecules expression NO2-dependent 0 0 0 0 0 0 IL. 12 Pathway activation in NK cells Bioactive Peptide 0 0 0 0 0 0 Induced Signaling Pathway sVEGFR1 −2.89576 1.5E−08 0.310332 0.974816 0.592 0.24173 CD133 0 0 0 0 0 0 expression rs2286455 rs3130 0 0 0 0 0 0 IL-6 plasma level 0 0 0 0 0 0 IL-8 plasma level 0 0 0 0 0 0 Child- Pugh class 0 0 0 0 0 0 HBV status 0 0 0 0 0 0 portal vein 0 0 0 thrombosis Sex 0 0 0 0 0 0 History of alcohol 0 0 0 0 0 0 intake Acneiform rash 0 0 0 0 0 0 angiopoietin-2 2.94843 0.12168 3.27E−06 −0.24052 0.360074 1.61E−14 expression levels EGFR expression 0.934068 0.009977 0.068077 0.001253 0.515136 −0.98413 levels Endothelin-1 −0.03232 0.002418 0.170778 −2.7E−06 0.890757 0.707517 expression levels angiopoietin-2 0 0 0 0 0 0 expression levels IL-12 plasma 0 0 0 0 0 0 level HGF plasma level 0 0 0 0 0 0 IL-16 plasma 0 0 0 0 0 0 level CXCL10 plasma 0 0 0 0 0 0 level SDF-1α plasma 0 0 0 0 0 0 level IL- 2Rα plasma 0 0 0 0 0 0 level IL-3 plasma level 0 0 0 0 0 0 IFN- α2 plasma 0 0 0 0 0 0 level TRAIL plasma 0 0 0 0 0 0 level M-CSF plasma 0 0 0 0 0 0 level PIGF plasma 0 0 0 0 0 0 level mucinous histology VEGF -1498 C> T 0 0 0 0 0 0 Liver metastasis ECOG 0 0 0 0 0 0 Performance 0 0 0 Status VEGF -1154 A> G 0 0 0 0 0 0 VEGF G-634C 0 0 0 0 0 0 ICAM1 T469C 0 0 0 0 0 0 WNK1- 0 0 0 0 0 0 rs11064560 0 0 0 EGF A-61G 0 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 0 VEGF-1154 G/ A 0 0 0 0 0 0 VEGF-2578 C/ A 0 0 0 0 0 0 rs699346 in 0 0 0 0 0 0 VEGFA rs 12505758 in 0 0 0 0 0 0 VEGFR2 0 0 0 0 0 0 VEGFR1 0 0 0 0 0 0 rs9582036 EGF rs444903 0 0 0 0 0 0 A>G IGF-1 rs6220 0 0 0 0 0 0 A>G CXCR1 0 0 0 0 0 0 rs2234671 G>C CXCR2 0 0 0 0 0 0 rs2230054 T>C EGFR rs2227983 0 0 0 0 0 0 G>A VEGFR-2 0 0 0 0 0 0 rs2305948 C>T IL-8 251 T>A 0 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 0 VEGF C936T 0 0 0 0 0 0 Adrenomedullin 0 0 0 0 0 0 Repeat Polymorphism VEGFA 2.259422 1.028465 1.81E−10 0 0.007774 0 ICAM1 2.516688 −3.6E−12 −0.9676 −0.00017 −2.45837 2.727169 Therapy Score −0.48458 −0.40637 −0.06459 0.297699 0.728342 0.84251 Patient ID GSM14718 60 80 74 77 55 Response: R R NR R R Timepoint: PT PT PT PT PT Number of resting 0.143095 −1.93425 1.318883 −1.7134 1.698203 circulating endothelial cells Number of total 0 0 0 0 0 circulating endothelial cells Expression of −0.0735 −4.8E−09 0.14841 1.195321 1.614482 PDGFR-beta Expression of 0 2.986855 0 0 2.741311 CD31 CDC16 level 3.4E−05 0.850735 1.787078 0.080641 1.974031 Lck and Fyn 2.49E−08 0.949367 −0.4284 0.082804 −0.98781 tyrosine kinases in initiation of TCR Activation pathway activation T Cell Receptor 0 0 0 0 0 Signaling Pathway activation T Helper Cell 0 0 0 0 0 Surface Molecules expression NO2-dependent 0 0 0 0 IL. 12 Pathway activation in NK cells Bioactive Peptide 0 0 0 0 0 Induced Signaling Pathway sVEGFR1 1.68231 −2.93689 −2.7E−10 −6.2E−08 −0.0023 CD133 0 0 0 0 0 expression rs2286455 0 0 0 0 0 rs3130 0 0 0 0 0 IL-6 plasma level 0 0 0 0 0 IL-8 plasma level Child-Pugh class HBV status 0 0 0 0 0 portal vein thrombosis Sex 0 0 0 0 0 History of alcohol 0 0 0 0 0 intake Acneiform rash 0 0 0 0 0 angiopoietin-2 0 0 0 0 0 expression levels EGFR expression 0 0 0 0 0 levels 0.000457 −0.42763 0.000343 −0.00322 −2.97733 Endothelin-1 expression levels 0.017333 0.376318 −0.27847 −0.92899 −0.08396 angiopoietin-2 expression levels 0.085635 −0.39897 0.077677 −0.99431 0.94965 IL-12 plasma level 0 0 0 0 0 HGF plasma level IL-16 plasma 0 0 0 0 0 level CXCL10 plasma 0 0 0 0 0 level 0 0 0 0 0 SDF-1α plasma level 0 0 0 0 0 IL- 2Rα plasma level 0 0 0 0 0 IL-3 plasma level IFN- α2 plasma 0 0 0 0 0 level TRAIL plasma 0 0 0 0 0 level 0 0 0 0 0 M-CSF plasma level 0 0 0 0 0 PIGF plasma level 0 0 0 0 0 mucinous histology 0 0 0 0 0 VEGF -1498 C>T Liver metastasis 0 0 0 0 0 ECOG Performance 0 0 0 0 0 Status 0 0 0 0 0 VEGF -1154 A>G VEGF G-634C 0 0 0 0 0 ICAM1 T469C WNK1- 0 0 0 0 0 rs11064560 0 0 0 0 0 EGF A-61G 0 0 0 0 0 CXCR2 C785T 0 0 0 0 0 VEGF-1154 G/A VEGF-2578 C/ A 0 0 0 0 0 rs699346 in 0 0 0 0 0 VEGFA 0 0 0 0 0 rs 12505758 in 0 0 0 0 0 VEGFR2 0 0 0 0 0 VEGFR1 rs9582036 0 0 0 0 0 EGF rs444903 A> G 0 0 0 0 0 IGF-1 rs6220 A> G 0 0 0 0 0 CXCR1 rs2234671 G> C 0 0 0 0 0 CXCR2 rs2230054 T> C 0 0 0 0 0 EGFR rs2227983 G> A 0 0 0 0 0 VEGFR-2 rs2305948 C> T 0 0 0 0 0 IL-8 251 T>A CXCR2 C785T 0 0 0 0 0 VEGF C936T Adrenomedullin 0 0 0 0 0 Repeat 0 0 0 0 0 Polymorphism 0 0 0 0 0 VEGFA 0 4.64E−06 0.182942 2.982064 0 ICAM1 −0.06574 2.997447 0.000147 2.144079 −0.00516 Therapy Score 1.789627 2.462987 2.808607 2.844987 3.021824 Abbreviations; NR—no response, PR—partial response, SD—stable disease, CR—complete response, and CPD—clinical progressive disease. -
- Hugo et al., Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma. Cell. 165, 35-44 (2016).
- Van Allen et al., Genomic Correlates of Response to CTLA-4 Blockade in Metastatic Melanoma. Science. 350(6257):302-22 (2015).
- In one aspect provided herein is a system, comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies, each of the therapy scores indicative of predicted response of the subject to administration of a respective therapy in the plurality of therapies.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies, each of the therapy scores indicative of predicted response of the subject to administration of a respective therapy in the plurality of therapies.
- In one aspect provided herein is a method, comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarker scores for the subject, wherein the subject subset of the plurality of biomarkers is a subset of the reference subset of the plurality of biomarkers; and determining, using the set of normalized biomarker scores for the subject, therapy scores for the plurality of therapies, each of the therapy scores indicative of predicted response of the subject to administration of a respective therapy in the plurality of therapies.
- In some embodiments, the plurality of biomarkers includes a first biomarker, and determining a normalized score for each biomarker in at least the subject subset of the plurality of biomarkers comprises: determining a first normalized score for the first biomarker using the distribution of values for the first biomarker. In some embodiments, determining the first normalized score comprises: determining a first un-normalized score for the first biomarker using the sequencing data; determining a first Z-score based on the first distribution of values for the first biomarker; and determining the first normalized score for the first biomarker based on the first un-normalized score and the first Z-score.
- In some embodiments, determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies as a sum of two or more scores in the set of normalized biomarker scores for the subject.
- In some embodiments, determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies at least in part by: determining weights for two or more scores in the set of normalized biomarker scores for the subject; and determining the first therapy score as a weighted sum of the two or more scores, summands of the sum being weighted by the determined weights.
- In some embodiments, determining the weights comprises determining the weights using a statistical model. In some embodiments, determining the weights comprises determining the weights using a generalized linear model. In some embodiments, determining the weights comprises determining the weights using a logistic regression model.
- In some embodiments, the plurality of therapies comprises a first therapy and a second therapy different from the first therapy, and wherein determining therapy scores for the plurality of therapies comprises: determining a first therapy score for the first therapy using a first subset of the set of normalized biomarker scores for the subject; and determining a second therapy score for the second therapy using a second subset of the set of normalized biomarker scores for the subject, wherein the second subset is different from the first subset.
- Some embodiments include providing the determined therapy scores to a user. Some embodiments include ranking the plurality of therapies based on the determined therapy scores. Some embodiments include recommending at least one of the plurality of therapies for the subject based on the determined therapy scores.
- In some embodiments, recommending the at least one of the plurality of therapies comprises: ranking the plurality of therapies based on the determined therapy scores; and recommending at least a threshold number of top-ranked therapies for the subject.
- In some embodiments, the plurality of therapies comprises at least two therapies selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
- In some embodiments, the plurality of biomarkers associated with the anti-PD1 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-CTLA4 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the IL-2 therapy comprises at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the IFN alpha therapy comprises at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-cancer vaccine therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-angiogenic therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-CD20 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, the anti-CD20 therapy is rituximab.
- Some embodiments further include generating a graphical user interface (GUI) comprising: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- In some embodiments, the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element.
- In some embodiments, in response to receiving, via the GUI, a user selection of the first therapy, presenting, via the GUI, information about at least one biomarker with which at least one of the first plurality of GUI elements is associated.
- In some embodiments, the first therapy is associated with a first therapy score and the second therapy is associated with a second therapy score, and wherein the first portion and the second portion are positioned, relative to one another in the GUI, based on relative magnitude of the first therapy score and the second therapy score.
- In some embodiments, each of the plurality of biomarkers is selected from the group consisting of: a genetic biomarker, a cellular biomarker, a saccharide biomarker, a lipid biomarker, a heterocyclic biomarker, an elementary compound biomarker, an imaging biomarker, an anthropological biomarker, a personal habit biomarker, a disease-state biomarker, and an expression biomarker. In some embodiments, the one or more genetic biomarkers includes a gene or marker described in the description and/or the figures.
- In some embodiments, one or more genetic biomarkers are selected from the group consisting of: interferons, cytotoxic proteins, enzymes, cell adhesion proteins, extracellular matrix proteins and polysaccharides, cell growth factors, cell differentiation factors, transcription factors, and intracellular signaling proteins. In some embodiments, the one or more genetic biomarkers is selected from the group consisting of: a cytokine, a chemokine, a chemokine receptor, and an interleukin. In some embodiments, the value of one or more cellular biomarkers is determined through analysis of the number of one or more types of cells or the percentage of one or more types of cells within the biological sample. In some embodiments, the one or more types of cells are selected from the group consisting of malignant cancerous cells, leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs). In some embodiments, the value of one or more expression biomarkers is determined through analysis of the expression level or enzymatic activity of the nucleic acid or protein of the expression biomarker.
- In some embodiments, the sequencing data is one or more of: DNA sequencing data, RNA sequencing data, or proteome sequencing data. In some embodiments, the sequencing data is obtained using one or more of the following techniques: whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray, DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP) genotyping.
- In some embodiments each of the at least one biological samples is a bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy. In some embodiments, the tissue biopsy comprises one or more samples from one or more tumors or tissues known or suspected of having cancerous cells.
- In some embodiments, the biomarker information also comprises results from one or more of the following types of analyses: blood analysis, cytometry analysis, histological analysis, immunohistological analysis, and patient history analysis.
- In some embodiments, each of the therapies are selected from the group consisting of: surgery, radiation therapy, chemotherapy, immunotherapy, viral therapy, targeted therapy, hormone therapy, transplants, phototherapy, cryotherapy, and hyperthermia. In some embodiments, each of the therapies are selected from immunotherapy and targeted therapy.
- In some embodiments, the therapy scores are indicative of response of the subject to administration of one therapy in the plurality of therapies. In some embodiments, the therapy scores are indicative of predicted response of the subject to administration of multiple therapies in the plurality of therapies.
- In one aspect provided herein is a system comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- In one aspect provided herein is a method, comprising: using at least one computer hardware processor to perform: obtaining first sequencing data about at least one biological sample of a subject prior to administration of a candidate therapy; obtaining second sequencing data about at least one other biological sample of the subject subsequent to administration of the candidate therapy; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of a plurality of biomarkers; determining, using the first and second sequencing data and the biomarker information, a first set of normalized biomarker scores for the subject and a second set of normalized biomarker scores for the subject; and determining, using the first and second sets of normalized biomarker scores for the subject, an impact score for the candidate therapy, wherein the impact score is indicative of response of the subject to administration of the candidate therapy.
- In some embodiments, determining the impact score for the candidate therapy further comprises: determining, using the first and second sets of normalized biomarker scores, a difference score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of biomarker difference scores for the subject; and determining, using the set of biomarker difference scores, the impact score for the candidate therapy.
- In some embodiments, determining the impact score for the candidate therapy further comprises: determining, using the first and second sets of normalized biomarker scores, a first and second subject subset score for the subject subset of the plurality of biomarkers determining a subject subset difference score, wherein the subject subset difference score is determined using the first and second subject subset score; and determining, using the subject subset difference score, the impact score for the candidate therapy.
- In some embodiments, the candidate therapy is selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
- In some embodiments, the plurality of biomarkers associated with the anti-PD1 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- In some embodiments, determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- In some embodiments, determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-CTLA4 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2. In some embodiments, determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2. In some embodiments, determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the IL-2 therapy comprises at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2. In some embodiments, determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2. In some embodiments, determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the IFN alpha therapy comprises at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2. In some embodiments, determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2. In some embodiments, determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-cancer vaccine therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2. In some embodiments, determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2. In some embodiments, determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-angiogenic therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2. In some embodiments, determining the biomarker difference scores for the subject comprises determining a difference score for each of at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2. In some embodiments, determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-CD20 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, wherein determining the biomarker difference scores for the subject comprises determining a difference score for at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, wherein determining the subject subset difference score for the subject comprises determining a first and second subject subset score for at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, the anti-CD20 therapy is rituximab.
- Some embodiments include generating a graphical user interface (GUI) comprising a first portion associated with the candidate therapy, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a difference score of the respective biomarker; and displaying the generated GUI.
- Some embodiments include generating a graphical user interface (GUI) comprising: a first portion associated with the candidate therapy, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a subject subset difference score; and displaying the generated GUI. In some embodiments, the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element. Some embodiments include, in response to receiving, via the GUI, a user selection of the candidate therapy, presenting, via the GUI, information about at least one biomarker with which at least one of the first plurality of GUI elements is associated.
- In some embodiments, determining the difference score for each biomarker in at least the subject subset comprises: determining a first normalized score for a first biomarker using the first sequencing data; determining a second normalized score for the first biomarker using the second sequencing data; and determining a first difference score based on a difference between the first and second normalized scores.
- In some embodiments, determining the difference score for each biomarker in at least the subject subset comprises: determining a first subject subset score for at least three biomarkers using the first sequencing data; determining a second subject subset score for at least three biomarkers using the second sequencing data; and determining a first subject subset difference score based on a difference between the first and second subject subset scores.
- In some embodiments, the biomarker information includes a first distribution of values for the first biomarker across a first group of people, and wherein determining the first normalized score comprises: determining a first un-normalized score for the first biomarker using the first sequencing data; determining a first Z-score based on the first distribution of values for the first biomarker; and determining the first normalized score for the first biomarker based on the first un-normalized score and the first Z-score.
- In one aspect provided herein is a system, comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized scores as input to the statistical model to obtain a second therapy score for the second therapy; generating a graphical user interface (GUI), wherein the GUI comprises: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized scores as input to the statistical model to obtain a second therapy score for the second therapy; generating a graphical user interface (GUI), wherein the GUI comprises: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- In one aspect provided herein is a method, comprising using the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker in at least a reference subset of a plurality of biomarkers across a respective group of people, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized scores as input to the statistical model to obtain a second therapy score for the second therapy; generating a graphical user interface (GUI), wherein the GUI comprises: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- In some embodiments, the plurality of biomarkers includes a first biomarker, and wherein determining a normalized score for each biomarker in at least the subject subset of the plurality of biomarkers comprises: determining a first normalized score for the first biomarker using the distribution of values for the first biomarker. In some embodiments, determining the first normalized score comprises: determining an un-normalized score for the first biomarker using the sequencing data; determining a Z-score based on the first distribution of values for the first biomarker; and determining a normalized score for the first biomarker based on the un-normalized score and the Z-score.
- In some embodiments, determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies as a sum of two or more scores in the set of normalized biomarker scores for the subject.
- In some embodiments, determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies at least in part by: determining weights for two or more scores in the set of normalized biomarker scores for the subject; and determining the first therapy score as a sum of the two or more scores, summands of the sum being weighted by the determined weights. In some embodiments, determining the weights comprises determining the weights using a machine learning technique. In some embodiments, determining the weights comprises determining the weights using a generalized linear model. In some embodiments, determining the weights comprises determining the weights using a logistic regression model.
- In some embodiments, the plurality of therapies comprises a first therapy and a second therapy different from the first therapy, and wherein determining therapy scores for the plurality of therapies comprises: determining a first therapy score for the first therapy using a first subset of the set of normalized biomarker scores for the subject; and determining a second therapy score for the second therapy using a second subset of the set of normalized biomarker scores for the subject, wherein the second subset is different from the first subset.
- Some embodiments include recommending at least one of the plurality of therapies for the subject based on the determined therapy scores. Some embodiments include ranking the plurality of therapies based on the determined therapy scores. In some embodiments, recommending the at least one of the plurality of therapies comprises: ranking the plurality of therapies based on the determined therapy scores; and recommending at least a threshold number of top-ranked therapies for the subject.
- In some embodiments, the plurality of therapies comprise at least two therapies selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
- In some embodiments, the plurality of biomarkers associated with the anti-PD1 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-CTLA4 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the IL-2 therapy comprises at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the IFN alpha therapy comprises at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-cancer vaccine therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-angiogenic therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- In some embodiments, the plurality of biomarkers associated with the anti-CD20 therapy comprises at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, the anti-CD20 therapy is rituximab.
- In some embodiments, the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element.
- In some embodiments, in response to receiving, via the GUI, a user selection of the first therapy, presenting, via the GUI, information about at least one biomarker with which at least one of the first plurality of GUI elements is associated.
- In some embodiments, the first therapy is associated with a first therapy score and the second therapy is associated with a second therapy score, and wherein the first portion and the second portion are positioned, relative to one another in the GUI, based on relative magnitude of the first therapy score and the second therapy score.
- In some embodiments, each of the plurality of biomarkers is selected from the group consisting of: a genetic biomarker, a cellular biomarker, a saccharide biomarker, a lipid biomarker, a heterocyclic biomarker, an elementary compound biomarker, an imaging biomarker, an anthropological biomarker, a personal habit biomarker, a disease-state biomarker, and an expression biomarker.
- In some embodiments, the value of one or more genetic biomarkers is determined through the identification of one or more mutations, insertions, deletions, rearrangements, fusions, copy number variations (CNV), or single nucleotide variants (SNV) in the nucleic acid or protein of the genetic biomarker.
- In some embodiments, the one or more genetic biomarkers includes a gene or marker described in the description and/or the figures.
- In some embodiments, one or more genetic biomarkers are selected from the group consisting of: interferons, cytotoxic proteins, enzymes, cell adhesion proteins, extracellular matrix proteins and polysaccharides, cell growth factors, cell differentiation factors, transcription factors, and intracellular signaling proteins.
- In some embodiments, the one or more genetic biomarkers is selected from the group consisting of: a cytokine, a chemokine, a chemokine receptor, and an interleukin.
- In some embodiments, the value of one or more cellular biomarkers is determined through analysis of the number of one or more types of cells or the percentage of one or more types of cells within the biological sample.
- In some embodiments, the one or more types of cells are selected from the group consisting of malignant cancerous cells, leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- In some embodiments, the value of one or more expression biomarkers is determined through analysis of the expression level or enzymatic activity of the nucleic acid or protein of the expression biomarker.
- In some embodiments, the sequencing data is one or more of: DNA sequencing data, RNA sequencing data, or proteome sequencing data. In some embodiments, the sequencing data is obtained using one or more of the following techniques: whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray, DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP) genotyping.
- In some embodiments, each of the at least one biological samples is a bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy. In some embodiments, the tissue biopsy comprises one or more samples from one or more tumors or tissues known or suspected of having cancerous cells.
- In some embodiments, the biomarker information also comprises results from one or more of the following types of analyses: blood analysis, cytometry analysis, histological analysis, immunohistological analysis, and patient history analysis.
- In some embodiments, each of the therapies are selected from the group consisting of: surgery, radiation therapy, chemotherapy, immunotherapy, viral therapy, targeted therapy, hormone therapy, transplants, phototherapy, cryotherapy, and hyperthermia.
- In some embodiments, each of the therapies are selected from immunotherapy and targeted therapy.
- In some embodiments, the therapy scores are indicative of response of the subject to administration of one therapy in the plurality of therapies. In some embodiments, the therapy scores are indicative of response of the subject to administration of multiple therapies in the plurality of therapies.
- In one aspect provided herein is a system, comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized biomarker scores as input to the statistical model to obtain a second therapy score for the second therapy; wherein the plurality of therapies comprise at least two therapies selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and wherein the plurality of biomarkers associated with each of the plurality of therapies comprises at least three biomarkers selected from the group of biomarkers associated with the respective therapy in Table 2.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized biomarker scores as input to the statistical model to obtain a second therapy score for the second therapy; wherein the plurality of therapies comprise at least two therapies selected from the group consisting of: an ani-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and wherein the plurality of biomarkers associated with each of the plurality of therapies comprises at least three biomarkers selected from the group of biomarkers associated with the respective therapy in Table 2.
- In one aspect provided herein is a method, comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one therapy in a plurality of therapies; determining, using the sequencing data and the biomarker information: a first set of normalized biomarker scores for a first set of biomarkers associated with a first therapy in the plurality of therapies; and a second set of normalized biomarker scores for a second set of biomarkers associated with a second therapy in the plurality of therapies, wherein the first set of biomarkers is different from the second set of biomarkers; providing the first set of normalized biomarker scores as input to a statistical model to obtain a first therapy score for the first therapy; providing the second set of normalized biomarker scores as input to the statistical model to obtain a second therapy score for the second therapy; wherein the plurality of therapies comprise at least two therapies selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy, and wherein the plurality of biomarkers associated with each of the plurality of therapies comprises at least three biomarkers selected from the group of biomarkers associated with the respective therapy in Table 2.
- In some embodiments, the plurality of biomarkers includes a first biomarker, and wherein determining a normalized score for each biomarker in at least the subject subset of the plurality of biomarkers comprises: determining a first normalized score for the first biomarker using the distribution of values for the first biomarker. In some embodiments, determining the first normalized score comprises: determining an un-normalized score for the first biomarker using the sequencing data; determining a Z-score based on the first distribution of values for the first biomarker; and determining a normalized score for the first biomarker based on the un-normalized score and the Z-score.
- In some embodiments, determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies as a sum of two or more scores in the set of normalized biomarker scores for the subject.
- In some embodiments, determining therapy scores for the plurality of therapies comprises determining a first therapy score for a first therapy in the plurality of therapies at least in part by: determining weights for two or more scores in the set of normalized biomarker scores for the subject; and determining the first therapy score as a sum of the two or more scores, summands of the sum being weighted by the determined weights.
- In some embodiments, determining the weights comprises determining the weights using a machine learning technique. In some embodiments, determining the weights comprises determining the weights using a generalized linear model. In some embodiments, determining the weights comprises determining the weights using a logistic regression model.
- In some embodiments, the plurality of therapies comprises a first therapy and a second therapy different from the first therapy, and wherein determining therapy scores for the plurality of therapies comprises: determining a first therapy score for the first therapy using a first subset of the set of normalized biomarker scores for the subject; and determining a second therapy score for the second therapy using a second subset of the set of normalized biomarker scores for the subject, wherein the second subset is different from the first subset.
- Some embodiments include recommending at least one of the plurality of therapies for the subject based on the determined therapy scores. In some embodiments, recommending the at least one of the plurality of therapies comprises: ranking the plurality of therapies based on the determined therapy scores; and recommending at least a threshold number of top-ranked therapies for the subject.
- In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-PD1 therapy in Table 2.
- In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CTLA4 therapy in Table 2.
- In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IL-2 therapy in Table 2.
- In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with IFN alpha therapy in Table 2.
- In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-cancer vaccine therapy in Table 2.
- In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-angiogenic therapy in Table 2.
- In some embodiments, determining the normalized biomarker scores for the subject comprises determining a normalized score for each of at least three biomarkers selected from the group of biomarkers associated with anti-CD20 therapy in Table 2. In some embodiments, the anti-CD20 therapy is rituximab.
- Some embodiments include generating a graphical user interface (GUI) comprising: a first portion associated with a first therapy in the plurality of therapies, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the first set of normalized scores; and a second portion associated with a second therapy in the plurality of therapies, the second portion including a second plurality of GUI elements different from the first plurality of GUI elements, each of the second plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a normalized score of the respective biomarker in the second set of normalized scores; and displaying the generated GUI.
- In some embodiments, the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element. Some embodiments include in response to receiving, via the GUI, a user selection of the first therapy, presenting, via the GUI, information about at least one biomarker with which at least one of the first plurality of GUI elements is associated.
- In some embodiments, the first therapy is associated with a first therapy score and the second therapy is associated with a second therapy score, and wherein the first portion and the second portion are positioned, relative to one another in the GUI, based on relative magnitude of the first therapy score and the second therapy score.
- In some embodiments, each of the plurality of biomarkers is selected from the group consisting of: a genetic biomarker, a cellular biomarker, a saccharide biomarker, a lipid biomarker, a heterocyclic biomarker, an elementary compound biomarker, an imaging biomarker, an anthropological biomarker, a personal habit biomarker, a disease-state biomarker, and an expression biomarker.
- In some embodiments, the value of one or more genetic biomarkers is determined through the identification of one or more mutations, insertions, deletions, rearrangements, fusions, copy number variations (CNV), or single nucleotide variants (SNV) in the nucleic acid or protein of the genetic biomarker. In some embodiments, the one or more genetic biomarkers includes a gene or marker described in the description and/or the figures. In some embodiments, one or more genetic biomarkers are selected from the group consisting of: interferons, cytotoxic proteins, enzymes, cell adhesion proteins, extracellular matrix proteins and polysaccharides, cell growth factors, cell differentiation factors, transcription factors, and intracellular signaling proteins. In some embodiments, the one or more genetic biomarkers is selected from the group consisting of: a cytokine, a chemokine, a chemokine receptor, and an interleukin.
- In some embodiments, the value of one or more cellular biomarkers is determined through analysis of the number of one or more types of cells or the percentage of one or more types of cells within the biological sample. In some embodiments, the one or more types of cells are selected from the group consisting of malignant cancerous cells, leukocytes, lymphocytes, stromal cells, vascular endothelial cells, vascular pericytes, and myeloid-derived suppressor cells (MDSCs).
- In some embodiments, the value of one or more expression biomarkers is determined through analysis of the expression level or enzymatic activity of the nucleic acid or protein of the expression biomarker.
- In some embodiments, the sequencing data is one or more of: DNA sequencing data, RNA sequencing data, or proteome sequencing data. In some embodiments, the sequencing data is obtained using one or more of the following techniques: whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray, DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP) genotyping.
- In some embodiments, each of the at least one biological samples is a bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy. In some embodiments, the tissue biopsy comprises one or more samples from one or more tumors or tissues known or suspected of having cancerous cells.
- In some embodiments, the biomarker information also comprises results from one or more of the following types of analyses: blood analysis, cytometry analysis, histological analysis, immunohistological analysis, and patient history analysis.
- In some embodiments, each of the therapies are selected from the group consisting of: surgery, radiation therapy, chemotherapy, immunotherapy, viral therapy, targeted therapy, hormone therapy, transplants, phototherapy, cryotherapy, and hyperthermia. In some embodiments, each of the therapies are selected from immunotherapy and targeted therapy.
- In some embodiments, the therapy scores are indicative of response of the subject to administration of one therapy in the plurality of therapies. In some embodiments, the therapy scores are indicative of response of the subject to administration of multiple therapies in the plurality of therapies.
- In one aspect provided herein is a system, comprising: at least one computer hardware processor; at least one database that stores biomarker information; and at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in the at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one or more cohorts in which the subject is a member.
- In one aspect provided herein is at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, cause the at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one or more cohorts in which the subject is a member.
- In one aspect a method comprising using at least one computer hardware processor to perform: obtaining sequencing data about at least one biological sample of a subject; accessing, in at least one database, biomarker information indicating a distribution of values for each biomarker, across a respective group of people, in at least a reference subset of the plurality of biomarkers, each of the plurality of biomarkers being associated with at least one candidate therapy; determining, using the sequencing data and the biomarker information, a normalized score for each biomarker in at least a subject subset of the plurality of biomarkers to obtain a set of normalized biomarkers for the subject; identifying the subject as a member of one or more cohorts based on the set of normalized biomarker scores for the subject, wherein each of the one or more cohorts is associated with a positive or negative outcome of the at least one candidate therapy; and outputting an indication of the one or more cohorts in which the subject is a member.
- In some embodiments, the at least one candidate therapy is associated with a clinical trial, optionally wherein the clinical trial is ongoing or the clinical trial is recruiting.
- In some embodiments, the positive outcome is an improvement in one or more aspects of a cancer or in one or more cancer symptoms.
- In some embodiments, the improvement in one or more aspects of a cancer or one or more cancer symptoms is selected from the group consisting of: decrease in tumor size, decrease in tumor number, decrease in number or percentage of cancerous cells in the body of the subject, and slowing of cancer growth.
- In some embodiments, the negative outcome is a cancer therapy-related adverse effect, an deterioration in one or more aspects of a cancer, or a deterioration in one or more cancer symptoms.
- In some embodiments, the cancer therapy-related adverse effect is selected from: cutaneous toxicity, thrombocytopenia, hepatotoxicity, neurotoxicity, nephrotoxicity, cardiotoxicity, hemorrhagic cystitis, immune-related toxicity, and death.
- In some embodiments, the deterioration in one or more aspects of a cancer or one or more cancer symptoms is selected from the group consisting of: increase in tumor size, increase in tumor number, increase in number or percentage of cancerous cells in the body of the subject, no slowing of cancer growth, and death.
- In some embodiments, the sequencing data is one or more of: DNA sequencing data, RNA sequencing data, or proteome sequencing data. In some embodiments, the sequencing data is obtained using one or more of the following techniques: whole genome sequencing (WGS), whole exome sequencing (WES), whole transcriptome sequencing, mRNA sequencing, DNA/RNA-hybridization, microarray, DNA/RNA chip, PCR, and single nucleotide polymorphism (SNP) genotyping.
- In some embodiments, the biological sample is from a tumor or tissue known or suspected of having cancerous cells. In some embodiments, each of the at least one biological samples is a bodily fluid, a cell sample, a liquid biopsy, or a tissue biopsy. In some embodiments, the biological sample is blood.
- Some embodiments include generating a graphical user interface (GUI) comprising: a first portion associated with the at least one candidate therapy, the first portion including a first plurality of GUI elements, each of the first plurality of GUI elements being associated with a respective biomarker in the plurality of biomarkers and having at least one visual characteristic determined based on a difference score of the respective biomarker; and displaying the generated GUI. In some embodiments, the at least one visual characteristic comprises color of a GUI element and/or size of the GUI element. Some embodiments include in response to receiving, via the GUI, a user selection of the at least one candidate therapy, presenting, via the GUI, information about at least one biomarker with which at least one of the first plurality of GUI elements is associated.
- The terms “program” or “software” are used herein in a generic sense to refer to any type of computer code or set of processor-executable instructions that can be employed to program a computer or other processor (physical or virtual) to implement various aspects of embodiments as discussed above. Additionally, according to one aspect, one or more computer programs that when executed perform methods of the technology described herein need not reside on a single computer or processor, but may be distributed in a modular fashion among different computers or processors to implement various aspects of the technology described herein.
- Processor-executable instructions may be in many forms, such as program modules, executed by one or more computers or other devices. Generally, program modules include routines, programs, objects, components, data structures, etc. that perform particular tasks or implement particular abstract data types. Typically, the functionality of the program modules may be combined or distributed.
- Also, data structures may be stored in one or more non-transitory computer-readable storage media in any suitable form. For simplicity of illustration, data structures may be shown to have fields that are related through location in the data structure. Such relationships may likewise be achieved by assigning storage for the fields with locations in a non-transitory computer-readable medium that convey relationship between the fields. However, any suitable mechanism may be used to establish relationships among information in fields of a data structure, including through the use of pointers, tags or other mechanisms that establish relationships among data elements.
- Various inventive concepts may be embodied as one or more processes, of which examples have been provided. The acts performed as part of each process may be ordered in any suitable way. Thus, embodiments may be constructed in which acts are performed in an order different than illustrated, which may include performing some acts simultaneously, even though shown as sequential acts in illustrative embodiments.
- As used herein in the specification and in the claims, the phrase “at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements. This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase “at least one” refers, whether related or unrelated to those elements specifically identified. Thus, for example, “at least one of A and B” (or, equivalently, “at least one of A or B,” or, equivalently “at least one of A and/or B”) can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
- The phrase “and/or,” as used herein in the specification and in the claims, should be understood to mean “either or both” of the elements so conjoined, i.e., elements that are conjunctively present in some cases and disjunctively present in other cases. Multiple elements listed with “and/or” should be construed in the same fashion, i.e., “one or more” of the elements so conjoined. Other elements may optionally be present other than the elements specifically identified by the “and/or” clause, whether related or unrelated to those elements specifically identified. Thus, as an example, a reference to “A and/or B”, when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
- In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
- Furthermore, the described methods and systems encompass all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the systems and methods described herein (or aspects thereof) are referred to as comprising particular elements and/or features, certain embodiments of the systems and methods or aspects of the same consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein.
- It is also noted that the terms “including,” “comprising,” “having,” “containing”, “involving”, are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the described systems and methods, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.
- Use of ordinal terms such as “first,” “second,” “third,” etc., in the claims to modify a claim element does not by itself connote any priority, precedence, or order of one claim element over another or the temporal order in which acts of a method are performed. Such terms are used merely as labels to distinguish one claim element having a certain name from another element having a same name (but for use of the ordinal term).
- Additionally, as used herein the terms “patient” and “subject” may be used interchangeably. Such terms may include, but are not limited to, human subjects or patients. Such terms may also include non-human primates or other animals.
- This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that fall within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the systems and methods described herein can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
- Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.
Claims (21)
1-30. (canceled)
31. A method, comprising:
using at least one computer hardware processor to perform:
obtaining sequencing data previously obtained by sequencing at least one biological sample of a subject;
obtaining biomarker information for multiple biomarkers including a first biomarker, each biomarker of the multiple biomarkers being associated with at least one therapy of multiple therapies, the first biomarker being associated with a first therapy of the multiple therapies, wherein the biomarker information includes, for each particular biomarker of the multiple biomarkers, a respective distribution of values for the particular biomarker, the biomarker information including a first distribution of values for the first biomarker;
determining, using the sequencing data, multiple biomarker scores including a respective biomarker score for each of at least some of the multiple biomarkers, the multiple biomarker scores including a first biomarker score for the first biomarker;
normalizing the multiple biomarker scores to a common scale using at least some of the biomarker information, thereby obtaining multiple normalized biomarker scores for the subject, the normalizing comprising:
normalizing the first biomarker score using the first distribution of values for the first biomarker to obtain a first normalized biomarker score for the subject;
determining therapy scores for at least some therapies of the multiple therapies using the multiple normalized biomarker scores, the determining comprising:
determining a first therapy score for the first therapy using at least some of the multiple normalized biomarker scores including the first normalized biomarker score; and
recommending, for the subject, at least one therapy of the at least some therapies based on the determined therapy scores,
wherein the at least one therapy is selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
32. The method of claim 31 , wherein normalizing the first biomarker using the first distribution of values for the first biomarker comprises:
determining a Z-score based on the first distribution of values for the first biomarker; and
normalizing the first biomarker score using the Z-score.
33. The method of claim 31 , wherein the multiple biomarkers include biomarkers associated with the first therapy, and wherein the at least some of the multiple normalized biomarker scores include normalized biomarker scores for the biomarkers associated with the first therapy.
34. The method of claim 33 , wherein the biomarkers associated with the first therapy include at least some biomarkers from the group of biomarkers associated with the first therapy in Table 2,
35. The method of claim 31 , wherein determining the first therapy score comprises:
determining a linear combination of the at least some of the multiple normalized biomarker scores.
36. The method of claim 31 , wherein determining the first therapy score comprises:
determining the first therapy score using a statistical model selected from the group consisting of a linear model, a generalized linear model, a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a mixture model, and a random forest regression model.
37. The method of claim 31 , further comprising:
administering the at least one therapy to the subject.
38. The method of claim 31 , wherein obtaining the sequencing data comprises obtaining the sequencing data at a first time point, and wherein the method further comprises:
obtaining second sequencing data about at least one second biological sample of the subject at a second time point after the first time point;
determining a second normalized biomarker score for the first biomarker using the second sequencing data; and
determining a difference between the first normalized biomarker score and the second normalized biomarker score.
39. The method of claim 38 , wherein the method further comprises:
administering the at least one therapy to the subject at a third time point between the first time point and the second time point.
40. A system, comprising:
at least one computer hardware processor; and
at least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by the at least one computer hardware processor, causes the at least one computer hardware processor to perform a method, comprising:
obtaining sequencing data about at least one biological sample of a subject;
obtaining sequencing data previously obtained by sequencing at least one biological sample of a subject;
obtaining biomarker information for multiple biomarkers including a first biomarker, each biomarker of the multiple biomarkers being associated with at least one therapy of multiple therapies, the first biomarker being associated with a first therapy of the multiple therapies, wherein the biomarker information includes, for each particular biomarker of the multiple biomarkers, a respective distribution of values for the particular biomarker, the biomarker information including a first distribution of values for the first biomarker;
determining, using the sequencing data, multiple biomarker scores including a respective biomarker score for each of at least some of the multiple biomarkers, the multiple biomarker scores including a first biomarker score for the first biomarker;
normalizing the multiple biomarker scores to a common scale using at least some of the biomarker information, thereby obtaining multiple normalized biomarker scores for the subject, the normalizing comprising:
normalizing the first biomarker score using the first distribution of values for the first biomarker to obtain a first normalized biomarker score for the subject;
determining therapy scores for at least some therapies of the multiple therapies using the multiple normalized biomarker scores, the determining comprising:
determining a first therapy score for the first therapy using at least some of the multiple normalized biomarker scores including the first normalized biomarker score; and
recommending, for the subject, at least one therapy of the at least some therapies based on the determined therapy scores,
wherein the at least one therapy is selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
41. The system of claim 40 , wherein normalizing the first biomarker using the first distribution of values for the first biomarker comprises:
determining a Z-score based on the first distribution of values for the first biomarker; and
normalizing the first biomarker score using the Z-score.
42. The system of claim 40 , wherein the multiple biomarkers include biomarkers associated with the first therapy, and wherein the at least some of the multiple normalized biomarker scores include normalized biomarker scores for the biomarkers associated with the first therapy.
43. The system of claim 40 , wherein determining the first therapy score comprises:
determining a linear combination of the at least some of the multiple normalized biomarker scores.
44. The system of claim 40 , wherein determining the first therapy score comprises:
determining the first therapy score using a statistical model selected from the group consisting of a linear model, a generalized linear model, a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a mixture model, and a random forest regression model.
45. The system of claim 40 , further comprising:
administering the at least one therapy to the subject.
46. At least one non-transitory computer-readable storage medium storing processor-executable instructions that, when executed by at least one computer hardware processor, causes the at least one computer hardware processor to perform a method, comprising:
obtaining sequencing data previously obtained by sequencing at least one biological sample of a subject;
obtaining biomarker information for multiple biomarkers including a first biomarker, each biomarker of the multiple biomarkers being associated with at least one therapy of multiple therapies, the first biomarker being associated with a first therapy of the multiple therapies, wherein the biomarker information includes, for each particular biomarker of the multiple biomarkers, a respective distribution of values for the particular biomarker, the biomarker information including a first distribution of values for the first biomarker;
determining, using the sequencing data, multiple biomarker scores including a respective biomarker score for each of at least some of the multiple biomarkers, the multiple biomarker scores including a first biomarker score for the first biomarker;
normalizing the multiple biomarker scores to a common scale using at least some of the biomarker information, thereby obtaining multiple normalized biomarker scores for the subject, the normalizing comprising:
normalizing the first biomarker score using the first distribution of values for the first biomarker to obtain a first normalized biomarker score for the subject;
determining therapy scores for at least some therapies of the multiple therapies using the multiple normalized biomarker scores, the determining comprising:
determining a first therapy score for the first therapy using at least some of the multiple normalized biomarker scores including the first normalized biomarker score; and
recommending, for the subject, at least one therapy of the at least some therapies based on the determined therapy scores,
wherein the at least one therapy is selected from the group consisting of: an anti-PD1 therapy, an anti-CTLA4 therapy, an IL-2 therapy, an IFN alpha therapy, an anti-cancer vaccine therapy, an anti-angiogenic therapy, and an anti-CD20 therapy.
47. The at least one non-transitory computer-readable storage medium of claim 46 , wherein normalizing the first biomarker using the first distribution of values for the first biomarker comprises:
determining a Z-score based on the first distribution of values for the first biomarker; and
normalizing the first biomarker score using the Z-score.
48. The at least one non-transitory computer-readable storage medium of claim 46 , wherein the multiple biomarkers include biomarkers associated with the first therapy, and wherein the at least some of the multiple normalized biomarker scores include normalized biomarker scores for the biomarkers associated with the first therapy.
49. The at least one non-transitory computer-readable storage medium of claim 46 , wherein determining the first therapy score comprises:
determining a linear combination of the at least some of the multiple normalized biomarker scores.
50. The at least one non-transitory computer-readable storage medium of claim 46 , wherein determining the first therapy score comprises:
determining the first therapy score using a statistical model selected from the group consisting of a linear model, a generalized linear model, a neural network model, a Bayesian regression model, an adaptive non-linear regression model, a mixture model, and a random forest regression model.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US18/460,330 US20240006029A1 (en) | 2017-06-13 | 2023-09-01 | Systems and methods for predicting therapy efficacy from normalized biomarker scores |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762518787P | 2017-06-13 | 2017-06-13 | |
US201762598440P | 2017-12-13 | 2017-12-13 | |
US16/006,340 US10340031B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/456,462 US11842797B2 (en) | 2017-06-13 | 2019-06-28 | Systems and methods for predicting therapy efficacy from normalized biomarker scores |
US18/460,330 US20240006029A1 (en) | 2017-06-13 | 2023-09-01 | Systems and methods for predicting therapy efficacy from normalized biomarker scores |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/456,462 Continuation US11842797B2 (en) | 2017-06-13 | 2019-06-28 | Systems and methods for predicting therapy efficacy from normalized biomarker scores |
Publications (1)
Publication Number | Publication Date |
---|---|
US20240006029A1 true US20240006029A1 (en) | 2024-01-04 |
Family
ID=62779138
Family Applications (27)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/006,572 Active US10650911B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,381 Abandoned US20180358125A1 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/006,462 Active 2040-08-30 US11367509B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,555 Active US10311967B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,279 Active US10340030B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/006,340 Active US10340031B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/006,200 Abandoned US20180358132A1 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/006,593 Active US11322226B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,481 Pending US20200175134A9 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,518 Active 2041-05-02 US11430545B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,085 Abandoned US20180357361A1 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying responders and non-responders to immune checkpoint blockade therapy |
US16/006,129 Active US10720230B2 (en) | 2017-06-13 | 2018-06-12 | Method for administering a checkpoint blockade therapy to a subject |
US16/391,221 Active US10395761B1 (en) | 2017-06-13 | 2019-04-22 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US29/694,308 Active USD891446S1 (en) | 2017-06-13 | 2019-06-10 | Display screen or portion thereof with graphical user interface |
US29/694,310 Active USD890779S1 (en) | 2017-06-13 | 2019-06-10 | Display screen or portion thereof with graphical user interface |
US16/456,462 Active 2039-04-29 US11842797B2 (en) | 2017-06-13 | 2019-06-28 | Systems and methods for predicting therapy efficacy from normalized biomarker scores |
US16/456,370 Active US10504615B2 (en) | 2017-06-13 | 2019-06-28 | Using cancer or pre-cancer subject sequencing data and a database of therapy biomarker distributions to determine normalized biomarker scores and generate a graphical user interface |
US16/523,808 Active US10580517B2 (en) | 2017-06-13 | 2019-07-26 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/662,280 Active US10636513B2 (en) | 2017-06-13 | 2019-10-24 | Using cancer or pre-cancer subject sequencing data and a database of therapy biomarker distributions to determine normalized biomarker scores and generate a graphical user interface |
US16/676,375 Active US10636514B2 (en) | 2017-06-13 | 2019-11-06 | Using subject sequencing data and a database of therapy biomarker distributions to determine normalized biomarker scores and therapy scores |
US16/696,128 Active US10706954B2 (en) | 2017-06-13 | 2019-11-26 | Systems and methods for identifying responders and non-responders to immune checkpoint blockade therapy |
US16/856,566 Active US11004542B2 (en) | 2017-06-13 | 2020-04-23 | Using subject sequencing data and a database of therapy biomarker distributions to determine therapy impact |
US16/871,755 Active US11302420B2 (en) | 2017-06-13 | 2020-05-11 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/920,226 Active US11373733B2 (en) | 2017-06-13 | 2020-07-02 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US17/237,672 Active US11705220B2 (en) | 2017-06-13 | 2021-04-22 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US17/699,018 Pending US20220389512A1 (en) | 2017-06-13 | 2022-03-18 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US18/460,330 Pending US20240006029A1 (en) | 2017-06-13 | 2023-09-01 | Systems and methods for predicting therapy efficacy from normalized biomarker scores |
Family Applications Before (26)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US16/006,572 Active US10650911B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,381 Abandoned US20180358125A1 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/006,462 Active 2040-08-30 US11367509B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,555 Active US10311967B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,279 Active US10340030B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/006,340 Active US10340031B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/006,200 Abandoned US20180358132A1 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US16/006,593 Active US11322226B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,481 Pending US20200175134A9 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,518 Active 2041-05-02 US11430545B2 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/006,085 Abandoned US20180357361A1 (en) | 2017-06-13 | 2018-06-12 | Systems and methods for identifying responders and non-responders to immune checkpoint blockade therapy |
US16/006,129 Active US10720230B2 (en) | 2017-06-13 | 2018-06-12 | Method for administering a checkpoint blockade therapy to a subject |
US16/391,221 Active US10395761B1 (en) | 2017-06-13 | 2019-04-22 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US29/694,308 Active USD891446S1 (en) | 2017-06-13 | 2019-06-10 | Display screen or portion thereof with graphical user interface |
US29/694,310 Active USD890779S1 (en) | 2017-06-13 | 2019-06-10 | Display screen or portion thereof with graphical user interface |
US16/456,462 Active 2039-04-29 US11842797B2 (en) | 2017-06-13 | 2019-06-28 | Systems and methods for predicting therapy efficacy from normalized biomarker scores |
US16/456,370 Active US10504615B2 (en) | 2017-06-13 | 2019-06-28 | Using cancer or pre-cancer subject sequencing data and a database of therapy biomarker distributions to determine normalized biomarker scores and generate a graphical user interface |
US16/523,808 Active US10580517B2 (en) | 2017-06-13 | 2019-07-26 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/662,280 Active US10636513B2 (en) | 2017-06-13 | 2019-10-24 | Using cancer or pre-cancer subject sequencing data and a database of therapy biomarker distributions to determine normalized biomarker scores and generate a graphical user interface |
US16/676,375 Active US10636514B2 (en) | 2017-06-13 | 2019-11-06 | Using subject sequencing data and a database of therapy biomarker distributions to determine normalized biomarker scores and therapy scores |
US16/696,128 Active US10706954B2 (en) | 2017-06-13 | 2019-11-26 | Systems and methods for identifying responders and non-responders to immune checkpoint blockade therapy |
US16/856,566 Active US11004542B2 (en) | 2017-06-13 | 2020-04-23 | Using subject sequencing data and a database of therapy biomarker distributions to determine therapy impact |
US16/871,755 Active US11302420B2 (en) | 2017-06-13 | 2020-05-11 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US16/920,226 Active US11373733B2 (en) | 2017-06-13 | 2020-07-02 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
US17/237,672 Active US11705220B2 (en) | 2017-06-13 | 2021-04-22 | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US17/699,018 Pending US20220389512A1 (en) | 2017-06-13 | 2022-03-18 | Systems and methods for generating, visualizing and classifying molecular functional profiles |
Country Status (12)
Country | Link |
---|---|
US (27) | US10650911B2 (en) |
EP (5) | EP3879535A1 (en) |
JP (8) | JP6812580B2 (en) |
KR (1) | KR102396784B1 (en) |
CN (2) | CN111052247A (en) |
AU (4) | AU2018102201A4 (en) |
CA (3) | CA3066004A1 (en) |
DE (1) | DE112018002990T5 (en) |
GB (5) | GB2577828A (en) |
IL (3) | IL270888A (en) |
SG (2) | SG10201911680SA (en) |
WO (3) | WO2018231772A1 (en) |
Families Citing this family (102)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2016205936A1 (en) * | 2015-06-22 | 2016-12-29 | Sunnybrook Research Institute | Systems and methods for prediction of tumor response to chemotherapy using pre-treatment quantitative ultrasound parameters |
US11497476B2 (en) * | 2015-06-22 | 2022-11-15 | Sunnybrook Research Institute | Systems and methods for prediction of tumor treatment response to using texture derivatives computed from quantitative ultrasound parameters |
WO2018098141A1 (en) | 2016-11-22 | 2018-05-31 | Hyperfine Research, Inc. | Systems and methods for automated detection in magnetic resonance images |
US10627464B2 (en) | 2016-11-22 | 2020-04-21 | Hyperfine Research, Inc. | Low-field magnetic resonance imaging methods and apparatus |
GB2577828A (en) | 2017-06-13 | 2020-04-08 | Bostongene Corp | Systems and methods for identifying cancer treatments from normalized biomarker scores |
US11505831B2 (en) * | 2017-12-20 | 2022-11-22 | Dana-Farber Cancer Institute, Inc. | Compositions and methods comprising digital signatures to predict response and resistance to targeted therapy and immunotherapy |
US11335464B2 (en) * | 2018-01-12 | 2022-05-17 | Siemens Medical Solutions Usa, Inc. | Integrated precision medicine by combining quantitative imaging techniques with quantitative genomics for improved decision making |
CN112292697A (en) | 2018-04-13 | 2021-01-29 | 弗里诺姆控股股份有限公司 | Machine learning embodiments for multi-analyte determination of biological samples |
US11475995B2 (en) | 2018-05-07 | 2022-10-18 | Perthera, Inc. | Integration of multi-omic data into a single scoring model for input into a treatment recommendation ranking |
US11348240B2 (en) | 2018-05-14 | 2022-05-31 | Tempus Labs, Inc. | Predicting total nucleic acid yield and dissection boundaries for histology slides |
US10957041B2 (en) | 2018-05-14 | 2021-03-23 | Tempus Labs, Inc. | Determining biomarkers from histopathology slide images |
US11348661B2 (en) | 2018-05-14 | 2022-05-31 | Tempus Labs, Inc. | Predicting total nucleic acid yield and dissection boundaries for histology slides |
US11741365B2 (en) | 2018-05-14 | 2023-08-29 | Tempus Labs, Inc. | Generalizable and interpretable deep learning framework for predicting MSI from histopathology slide images |
US11348239B2 (en) | 2018-05-14 | 2022-05-31 | Tempus Labs, Inc. | Predicting total nucleic acid yield and dissection boundaries for histology slides |
US11574718B2 (en) * | 2018-05-31 | 2023-02-07 | Perthera, Inc. | Outcome driven persona-typing for precision oncology |
USD887431S1 (en) * | 2018-06-18 | 2020-06-16 | Genomic Prediction, Inc. | Display screen with graphical user interface |
USD896241S1 (en) * | 2018-12-03 | 2020-09-15 | Illumina, Inc. | Display screen or portion thereof with graphical user interface |
CN109712716B (en) * | 2018-12-25 | 2021-08-31 | 广州医科大学附属第一医院 | Disease influence factor determination method, system and computer equipment |
CA3125386A1 (en) * | 2018-12-31 | 2020-07-09 | Tempus Labs, Inc. | Transcriptome deconvolution of metastatic tissue samples |
USD910706S1 (en) * | 2019-01-31 | 2021-02-16 | Driv Ip, Llc | Display screen with graphical user interface |
WO2020172591A1 (en) * | 2019-02-22 | 2020-08-27 | Mitra Rxdx, Inc. | A method to predict a patient's response to an anti-cancer drug from an expression level of a set of genes |
WO2020176620A1 (en) * | 2019-02-26 | 2020-09-03 | Tempus | Systems and methods for using sequencing data for pathogen detection |
CN111621564B (en) * | 2019-02-28 | 2022-03-25 | 武汉大学 | Method for identifying effective tumor neoantigen |
EP3935581A4 (en) | 2019-03-04 | 2022-11-30 | Iocurrents, Inc. | Data compression and communication using machine learning |
WO2020231937A1 (en) * | 2019-05-10 | 2020-11-19 | University Of Massachusetts | Irf2 as a prognostic biomarker and target for augmenting immunotherapy |
EP3970152A4 (en) | 2019-05-14 | 2023-07-26 | Tempus Labs, Inc. | Systems and methods for multi-label cancer classification |
USD892825S1 (en) | 2019-06-10 | 2020-08-11 | Bostongene Corporation | Display screen or portion thereof with graphical user interface |
USD891445S1 (en) | 2019-06-10 | 2020-07-28 | Bostongene Corporation | Display screen or portion thereof with graphical user interface |
WO2020249704A1 (en) * | 2019-06-13 | 2020-12-17 | F. Hoffmann-La Roche Ag | Systems and methods with improved user interface for interpreting and visualizing longitudinal data |
CN110309382B (en) * | 2019-06-17 | 2021-05-28 | 暨南大学 | Mobile application homology edge clustering method based on multi-dimensional features |
WO2021003246A1 (en) * | 2019-07-01 | 2021-01-07 | Accure Health Inc. | Predictive liquid markers for cancer immunotherapy |
EP3994696A2 (en) | 2019-07-03 | 2022-05-11 | BostonGene Corporation | Systems and methods for sample preparation, sample sequencing, and sequencing data bias correction and quality control |
AU2020313915A1 (en) * | 2019-07-12 | 2022-02-24 | Tempus Ai, Inc. | Adaptive order fulfillment and tracking methods and systems |
US10581851B1 (en) * | 2019-07-17 | 2020-03-03 | Capital One Services, Llc | Change monitoring and detection for a cloud computing environment |
US11379757B2 (en) * | 2019-07-31 | 2022-07-05 | BioSymetrics, Inc. | Methods, systems, and frameworks for data analytics using machine learning |
CN110277135B (en) * | 2019-08-10 | 2021-06-01 | 杭州新范式生物医药科技有限公司 | Method and system for selecting individualized tumor neoantigen based on expected curative effect |
WO2021030193A1 (en) * | 2019-08-13 | 2021-02-18 | Nantomics, Llc | System and method for classifying genomic data |
CA3148023A1 (en) | 2019-08-16 | 2021-02-25 | Nike T. Beaubier | Systems and methods for detecting cellular pathway dysregulation in cancer specimens |
CN110716171A (en) * | 2019-08-28 | 2020-01-21 | 上海无线电设备研究所 | Polarization DOA joint estimation method based on genetic algorithm |
EP3799057A1 (en) * | 2019-09-25 | 2021-03-31 | Koninklijke Philips N.V. | Prediction tool for patient immune response to a therapy |
WO2021062200A1 (en) * | 2019-09-27 | 2021-04-01 | The Regents Of The University Of Colorado, A Body Corporate | Enhancing cancer therapy treatment with bh3 mimetics |
WO2021076960A1 (en) * | 2019-10-16 | 2021-04-22 | Anand Rene | Live virus vaccine injury risk |
WO2021096888A1 (en) * | 2019-11-12 | 2021-05-20 | Foundation Medicine, Inc. | Methods of detecting a fusion gene encoding a neoantigen |
CN110938627B (en) * | 2019-11-25 | 2021-07-06 | 西安交通大学第二附属医院 | Use of an ESCO2 inhibitor for the manufacture of a medicament for the treatment of hypopharyngeal cancer |
TWI709904B (en) * | 2019-11-26 | 2020-11-11 | 國立中央大學 | Methods for training an artificial neural network to predict whether a subject will exhibit a characteristic gene expression and systems for executing the same |
JP2023504555A (en) | 2019-12-05 | 2023-02-03 | ボストンジーン コーポレイション | Machine learning techniques for gene expression analysis |
CN112574309B (en) * | 2019-12-05 | 2023-06-16 | 启愈生物技术(上海)有限公司 | anti-PD-L1 nano antibody and application thereof |
CA3163492A1 (en) | 2019-12-12 | 2021-06-17 | Tempus Labs, Inc. | Real-world evidence of diagnostic testing and treatment patterns in u.s. breast cancer patients |
JP2023509540A (en) * | 2020-01-07 | 2023-03-08 | コリア アドバンスド インスティテュート オブ サイエンス アンド テクノロジー | Methods, systems and uses thereof for screening neoantigens |
US20230054656A1 (en) * | 2020-02-05 | 2023-02-23 | Board Of Regents, The University Of Texas System | Diagnostic and prognostic utility of exosomes in immunotherapy |
CN111292542B (en) * | 2020-02-24 | 2021-08-31 | 深圳市综合交通设计研究院有限公司 | Signal lamp system and control method thereof |
CN111354420B (en) * | 2020-03-08 | 2020-12-22 | 吉林大学 | siRNA research and development method for COVID-19 virus drug therapy |
US20210363592A1 (en) * | 2020-03-11 | 2021-11-25 | Vanderbilt University | Detection of Signatures in a Breast Cancer Subject |
EP4121769A4 (en) | 2020-03-19 | 2024-03-20 | Chugai Pharmaceutical Co Ltd | Biomarkers for predicting the response to checkpoint inhibitors |
WO2021205274A1 (en) * | 2020-04-08 | 2021-10-14 | Immunitybio, Inc. | Methods for assessing chemokine activity |
CA3177323A1 (en) * | 2020-04-30 | 2021-11-04 | Caris Mpi, Inc. | Immunotherapy response signature |
TW202211250A (en) * | 2020-05-26 | 2022-03-16 | 南韓商愛思阿爾法數字醫療科技有限公司 | System for treating cancer cachexia, computing system for treating cancer cachexia and operating method thereof, and non-transitory readable medium |
CN111863137B (en) * | 2020-05-28 | 2024-01-02 | 上海朴岱生物科技合伙企业(有限合伙) | Complex disease state evaluation method based on high-throughput sequencing data and clinical phenotype construction and application |
CN111755073B (en) * | 2020-05-31 | 2022-11-15 | 复旦大学 | Transcriptome-based PD-1 therapy treatment effect prediction system |
JP2021197100A (en) * | 2020-06-18 | 2021-12-27 | 国立研究開発法人産業技術総合研究所 | Information processing system, information processing method, identification method and program |
CN111863120B (en) * | 2020-06-28 | 2022-05-13 | 深圳晶泰科技有限公司 | Medicine virtual screening system and method for crystal compound |
WO2022010866A1 (en) | 2020-07-06 | 2022-01-13 | Bostongene Corporation | Tumor microenvironment-based methods for assessing car-t and other immunotherapies |
WO2022016447A1 (en) * | 2020-07-23 | 2022-01-27 | 碳逻辑生物科技(香港)有限公司 | Marker for assessing responsiveness of colorectal cancer patients to immunotherapeutic drug |
EP4186063A1 (en) * | 2020-07-23 | 2023-05-31 | The DNA Company Inc. | Systems and methods for determining a physiological profile using genetic information |
WO2022031620A2 (en) * | 2020-08-01 | 2022-02-10 | Aigene | Methods for the rapid assessment of the efficacy of cancer therapy and related applications |
CN112147326B (en) * | 2020-09-04 | 2022-04-08 | 北京大学 | Accurate detection kit for tumor immune cell subset typing |
CN112086199B (en) * | 2020-09-14 | 2023-06-09 | 中科院计算所西部高等技术研究院 | Liver cancer data processing system based on multiple groups of study data |
WO2022089426A1 (en) * | 2020-10-27 | 2022-05-05 | 细胞图谱有限公司 | Method for analyzing peripheral blood sample and kit |
CN112637134A (en) * | 2020-12-02 | 2021-04-09 | 电子科技大学 | Signal sorting method for time hopping signals of data link communication system |
CN112530581B (en) * | 2020-12-03 | 2023-11-21 | 安徽医科大学第一附属医院 | Immune molecule classification system for prostate cancer patients and application thereof |
TWD216917S (en) | 2020-12-11 | 2022-02-01 | 股感媒體科技股份有限公司 | Graphical User Interface for Display Panel |
US20220186318A1 (en) | 2020-12-11 | 2022-06-16 | Bostongene Corporation | Techniques for identifying follicular lymphoma types |
CN112635063B (en) * | 2020-12-30 | 2022-05-24 | 华南理工大学 | Comprehensive lung cancer prognosis prediction model, construction method and device |
WO2022159569A1 (en) * | 2021-01-20 | 2022-07-28 | Memorial Sloan Kettering Cancer Center | Peripheral blood phenotype linked to outcomes after immunotherapy treatment |
JP2022112097A (en) * | 2021-01-21 | 2022-08-02 | キヤノンメディカルシステムズ株式会社 | Medical information processing apparatus |
CN112735520B (en) * | 2021-02-03 | 2021-07-20 | 深圳裕康医学检验实验室 | Interpretation method, system and storage medium for tumor individualized immunotherapy gene detection result |
WO2022192857A1 (en) * | 2021-03-08 | 2022-09-15 | Venn Biosciences Corporation | Biomarkers for determining an immuno-onocology response |
CN112863595A (en) * | 2021-03-08 | 2021-05-28 | 中国农业科学院兰州畜牧与兽药研究所 | Method for excavating Tibetan sheep high-altitude hypoxia adaptability related gene based on MeRIP-Seq technology |
JP2024509273A (en) | 2021-03-09 | 2024-02-29 | ボストンジーン コーポレイション | B cell-rich tumor microenvironment |
US20220319638A1 (en) | 2021-03-09 | 2022-10-06 | Bostongene Corporation | Predicting response to treatments in patients with clear cell renal cell carcinoma |
US20220290254A1 (en) * | 2021-03-09 | 2022-09-15 | Bostongene Corporation | B cell-enriched tumor microenvironments |
EP4305191A1 (en) * | 2021-03-12 | 2024-01-17 | Pragma Biosciences Inc. | Systems and methods for identifying microbial biosynthetic genetic clusters |
CN112698044B (en) * | 2021-03-23 | 2021-06-22 | 信纳克(北京)生化标志物检测医学研究有限责任公司 | Device and method for evaluating immune state after targeted therapy |
US11931127B1 (en) | 2021-04-08 | 2024-03-19 | T-Mobile Usa, Inc. | Monitoring users biological indicators using a 5G telecommunication network |
EP4341939A1 (en) | 2021-05-18 | 2024-03-27 | BostonGene Corporation | Techniques for single sample expression projection to an expression cohort sequenced with another protocol |
IL310769A (en) * | 2021-08-11 | 2024-04-01 | Oncohost Ltd | Predicting patient response |
WO2023055657A1 (en) * | 2021-09-30 | 2023-04-06 | Selonterra, Inc. | Use of c9orf72 -mediated genes for diagnosis and treatment of neuronal diseases |
WO2023076574A1 (en) | 2021-10-29 | 2023-05-04 | Bostongene Corporation | Tumor microenvironment types in breast cancer |
WO2023089597A2 (en) * | 2021-11-22 | 2023-05-25 | Venn Biosciences Corporation | Predicting sarcoma treatment response using targeted quantification of site-specific protein glycosylation |
WO2023097300A1 (en) * | 2021-11-23 | 2023-06-01 | Curematch Inc. | Clinical trial optimization |
US20230178200A1 (en) * | 2021-12-03 | 2023-06-08 | Digital Diagnostics Inc. | Direct medical treatment predictions using artificial intelligence |
WO2023137401A1 (en) * | 2022-01-13 | 2023-07-20 | Synthorx, Inc. | Methods for selecting subjects and treating cancer with il-2 therapy |
WO2023154549A1 (en) | 2022-02-14 | 2023-08-17 | Bostongene Corporation | Urothelial tumor microenvironment (tme) types |
WO2023194090A1 (en) | 2022-04-08 | 2023-10-12 | Bayer Aktiengesellschaft | Multiple instance learning considering neighborhood aggregations |
WO2023208663A1 (en) | 2022-04-26 | 2023-11-02 | Bayer Aktiengesellschaft | Multiple-instance learning based on regional embeddings |
WO2023213623A1 (en) | 2022-05-03 | 2023-11-09 | Bayer Aktiengesellschaft | Dynamic sampling strategy for multiple-instance learning |
WO2024025923A1 (en) * | 2022-07-26 | 2024-02-01 | Washington University | Methods for selection of cancer patients for anti-angiogenic and immune checkpoint blockade therapies and combinations thereof |
WO2024033930A1 (en) * | 2022-08-11 | 2024-02-15 | OncoHost Ltd. | Predicting patient response |
WO2024054951A1 (en) * | 2022-09-08 | 2024-03-14 | Cardiff Oncology, Inc. | Methods of monitoring mutations in treatment of colorectal cancer |
CN116248680B (en) * | 2023-05-11 | 2023-08-01 | 湖南工商大学 | De novo peptide sequencing method, de novo peptide sequencing device and related equipment |
CN117095743B (en) * | 2023-10-17 | 2024-01-05 | 山东鲁润阿胶药业有限公司 | Polypeptide spectrum matching data analysis method and system for small molecular peptide donkey-hide gelatin |
CN117542529B (en) * | 2024-01-10 | 2024-04-02 | 北京博富瑞基因诊断技术有限公司 | Method, system, device and storage medium for predicting non-recurrent death risk of HLA-incompatible allogeneic hematopoietic stem cell transplantation |
Family Cites Families (166)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US280468A (en) * | 1883-07-03 | Carrier for store-service apparatus | ||
US4777127A (en) | 1985-09-30 | 1988-10-11 | Labsystems Oy | Human retrovirus-related products and methods of diagnosing and treating conditions associated with said retrovirus |
GB8702816D0 (en) | 1987-02-07 | 1987-03-11 | Al Sumidaie A M K | Obtaining retrovirus-containing fraction |
US5219740A (en) | 1987-02-13 | 1993-06-15 | Fred Hutchinson Cancer Research Center | Retroviral gene transfer into diploid fibroblasts for gene therapy |
US5422120A (en) | 1988-05-30 | 1995-06-06 | Depotech Corporation | Heterovesicular liposomes |
AP129A (en) | 1988-06-03 | 1991-04-17 | Smithkline Biologicals S A | Expression of retrovirus gag protein eukaryotic cells |
WO1990007936A1 (en) | 1989-01-23 | 1990-07-26 | Chiron Corporation | Recombinant therapies for infection and hyperproliferative disorders |
ES2200016T3 (en) | 1989-03-21 | 2004-03-01 | Vical Incorporated | EXPRESSION OF EXECUTIVE POLINUCLEOTIDIC SEQUENCES IN A VERTEBRATE. |
US5703055A (en) | 1989-03-21 | 1997-12-30 | Wisconsin Alumni Research Foundation | Generation of antibodies through lipid mediated DNA delivery |
EP1001032A3 (en) | 1989-08-18 | 2005-02-23 | Chiron Corporation | Recombinant retroviruses delivering vector constructs to target cells |
US5585362A (en) | 1989-08-22 | 1996-12-17 | The Regents Of The University Of Michigan | Adenovirus vectors for gene therapy |
ZA911974B (en) | 1990-03-21 | 1994-08-22 | Res Dev Foundation | Heterovesicular liposomes |
WO1993003769A1 (en) | 1991-08-20 | 1993-03-04 | THE UNITED STATES OF AMERICA, represented by THE SECRETARY, DEPARTEMENT OF HEALTH AND HUMAN SERVICES | Adenovirus mediated transfer of genes to the gastrointestinal tract |
WO1993010218A1 (en) | 1991-11-14 | 1993-05-27 | The United States Government As Represented By The Secretary Of The Department Of Health And Human Services | Vectors including foreign genes and negative selective markers |
GB9125623D0 (en) | 1991-12-02 | 1992-01-29 | Dynal As | Cell modification |
FR2688514A1 (en) | 1992-03-16 | 1993-09-17 | Centre Nat Rech Scient | Defective recombinant adenoviruses expressing cytokines and antitumour drugs containing them |
JPH07507689A (en) | 1992-06-08 | 1995-08-31 | ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア | Specific tissue targeting methods and compositions |
JPH09507741A (en) | 1992-06-10 | 1997-08-12 | アメリカ合衆国 | Vector particles resistant to inactivation by human serum |
GB2269175A (en) | 1992-07-31 | 1994-02-02 | Imperial College | Retroviral vectors |
EP1024198A3 (en) | 1992-12-03 | 2002-05-29 | Genzyme Corporation | Pseudo-adenoviral vectors for the gene therapy of haemophiliae |
US5981568A (en) | 1993-01-28 | 1999-11-09 | Neorx Corporation | Therapeutic inhibitor of vascular smooth muscle cells |
WO1994023697A1 (en) | 1993-04-22 | 1994-10-27 | Depotech Corporation | Cyclodextrin liposomes encapsulating pharmacologic compounds and methods for their use |
AU687829B2 (en) | 1993-06-24 | 1998-03-05 | Advec, Inc. | Adenovirus vectors for gene therapy |
ATE215989T1 (en) | 1993-09-15 | 2002-04-15 | Chiron Corp | RECOMBINANT ALPHAVIRUS VECTOR |
US6015686A (en) | 1993-09-15 | 2000-01-18 | Chiron Viagene, Inc. | Eukaryotic layered vector initiation systems |
SK283703B6 (en) | 1993-10-25 | 2003-12-02 | Canji, Inc. | Recombinant adenoviral vector and methods of use |
CN1099868C (en) | 1993-11-16 | 2003-01-29 | 斯卡法玛公司 | Vesicles with controlled release of actives |
JP4303315B2 (en) | 1994-05-09 | 2009-07-29 | オックスフォード バイオメディカ(ユーケー)リミテッド | Non-crossing retroviral vector |
WO1996017072A2 (en) | 1994-11-30 | 1996-06-06 | Chiron Viagene, Inc. | Recombinant alphavirus vectors |
EP0953052B1 (en) | 1996-05-06 | 2009-03-04 | Oxford BioMedica (UK) Limited | Crossless retroviral vectors |
WO2000053211A2 (en) | 1999-03-09 | 2000-09-14 | University Of Southern California | Method of promoting myocyte proliferation and myocardial tissue repair |
US7905134B2 (en) | 2002-08-06 | 2011-03-15 | The Regents Of The University Of California | Biomarker normalization |
CA2516182A1 (en) | 2003-02-28 | 2004-09-16 | Bayer Pharmaceuticals Corporation | Expression profiles for breast cancer and methods of use |
USD496297S1 (en) * | 2003-11-13 | 2004-09-21 | Susan M. Kahil | Face for a timepiece |
US7858323B2 (en) | 2004-06-09 | 2010-12-28 | The Regents Of The University Of Michigan | Phage microarray profiling of the humoral response to disease |
US7862995B2 (en) | 2004-12-10 | 2011-01-04 | Targeted Molecular Diagnostics | Methods and materials for predicting responsiveness to treatment with dual tyrosine kinase inhibitor |
WO2006133460A2 (en) * | 2005-06-09 | 2006-12-14 | Yale University | Methods for diagnosing and treating breast cancer based on a her/er ratio |
WO2007038792A2 (en) * | 2005-09-28 | 2007-04-05 | H. Lee Moffitt Cancer Center | Individualized cancer treatments |
US9347945B2 (en) * | 2005-12-22 | 2016-05-24 | Abbott Molecular Inc. | Methods and marker combinations for screening for predisposition to lung cancer |
NZ544432A (en) * | 2005-12-23 | 2009-07-31 | Pacific Edge Biotechnology Ltd | Prognosis prediction for colorectal cancer using a prognositc signature comprising markers ME2 and FAS |
US8068994B2 (en) | 2007-07-27 | 2011-11-29 | Wayne State University | Method for analyzing biological networks |
NZ562237A (en) * | 2007-10-05 | 2011-02-25 | Pacific Edge Biotechnology Ltd | Proliferation signature and prognosis for gastrointestinal cancer |
US20090105167A1 (en) | 2007-10-19 | 2009-04-23 | Duke University | Predicting responsiveness to cancer therapeutics |
CA2726531A1 (en) | 2008-06-05 | 2009-12-10 | University Health Network | Compositions and methods for classifying lung cancer and prognosing lung cancer survival |
CN102040569B (en) | 2009-10-20 | 2012-11-07 | 北京绿色金可生物技术股份有限公司 | Carotinoid derivatives and preparation method and application thereof |
CA2782620A1 (en) * | 2009-12-01 | 2011-06-09 | Compendia Bioscience, Inc. | Classification of cancers |
WO2011085276A2 (en) * | 2010-01-09 | 2011-07-14 | The Translational Genomics Research Institute | Methods and kits to predict prognostic and therapeutic outcome in small cell lung cancer |
USD697080S1 (en) * | 2010-02-26 | 2014-01-07 | Draeger Medical Systems, Inc. | Display screen with an icon |
US9400958B2 (en) * | 2010-06-30 | 2016-07-26 | Oracle International Corporation | Techniques for display of information related to policies |
LT3141617T (en) | 2011-01-11 | 2019-02-25 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for predicting the outcome of a cancer in a patient by analysing gene expression |
CN103649959B (en) * | 2011-03-10 | 2019-11-19 | 美迪生健康有限公司 | Improve the system of health care |
WO2012167278A1 (en) * | 2011-06-02 | 2012-12-06 | Almac Diagnostics Limited | Molecular diagnostic test for cancer |
EP2717901A4 (en) * | 2011-06-06 | 2015-01-21 | Women And Infants Hospital Of Rhode Island | He4 based therapy for malignant disease |
WO2012170715A1 (en) * | 2011-06-07 | 2012-12-13 | Caris Mpi, Inc. | Molecular profiling for cancer |
WO2012170710A1 (en) * | 2011-06-08 | 2012-12-13 | Altheadx Incorporated | Disease classification modules |
AU2012271516A1 (en) * | 2011-06-16 | 2014-01-23 | Caris Life Sciences Switzerland Holdings Gmbh | Biomarker compositions and methods |
WO2013030841A1 (en) * | 2011-09-04 | 2013-03-07 | Yissum Research Development Company Of The Hebrew Universitiy Of Jerusalem Ltd. | Prognostic methods and compositions for predicting interferon treatment eficacy in a subject |
EP2794911A1 (en) * | 2011-12-22 | 2014-10-29 | Aveo Pharmaceuticals, Inc. | Identification of multigene biomarkers |
DK3435084T3 (en) * | 2012-08-16 | 2023-05-30 | Mayo Found Medical Education & Res | PROSTATE CANCER PROGNOSIS USING BIOMARKERS |
USD743413S1 (en) * | 2012-09-19 | 2015-11-17 | ABBYY InfoPiosk LLC | Display screen or portion thereof with graphical user interface |
WO2014087156A1 (en) * | 2012-12-03 | 2014-06-12 | Almac Diagnostics Limited | Molecular diagnostic test for cancer |
USD719177S1 (en) * | 2012-12-27 | 2014-12-09 | Jason M. Cohen | Display screen or portion thereof with graphical user interface |
CN105144179B (en) * | 2013-01-29 | 2019-05-17 | 分子健康股份有限公司 | System and method for clinical decision support |
USD735732S1 (en) * | 2013-03-12 | 2015-08-04 | Hewlett-Packard Development Company, L.P. | Display screen with graphical user interface |
EP2787670A1 (en) | 2013-04-05 | 2014-10-08 | Panasonic Intellectual Property Corporation of America | MCS table adaptation for 256-QAM |
USD725148S1 (en) * | 2013-04-30 | 2015-03-24 | Microsoft Corporation | Display screen with animated icon |
US10679730B2 (en) * | 2013-05-28 | 2020-06-09 | The University Of Chicago | Prognostic and predictive breast cancer signature |
USD741912S1 (en) * | 2013-05-29 | 2015-10-27 | Microsoft Corporation | Display screen with animated graphical user interface |
USD743423S1 (en) * | 2013-06-04 | 2015-11-17 | Abbyy Infopoisk Llc | Display screen or portion thereof with graphical user interface |
USD743424S1 (en) * | 2013-06-04 | 2015-11-17 | Abbyy Infopoisk Llc | Display screen or portion thereof with graphical user interface |
USD805535S1 (en) * | 2013-06-04 | 2017-12-19 | Abbyy Production Llc | Display screen or portion thereof with a transitional graphical user interface |
USD755240S1 (en) * | 2013-06-09 | 2016-05-03 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD819649S1 (en) * | 2013-06-09 | 2018-06-05 | Apple Inc. | Display screen or portion thereof with graphical user interface |
US10190169B2 (en) | 2013-06-20 | 2019-01-29 | Immunexpress Pty Ltd | Biomarker identification |
USD744500S1 (en) * | 2013-07-05 | 2015-12-01 | Lg Electronics Inc. | Display screen with transitional graphical user interface |
EP3019865A4 (en) * | 2013-07-12 | 2017-04-05 | Immuneering Corporation | Systems, methods, and environment for automated review of genomic data to identify downregulated and/or upregulated gene expression indicative of a disease or condition |
USD708193S1 (en) * | 2013-08-30 | 2014-07-01 | Nike, Inc. | Display screen with graphical user interface |
USD746831S1 (en) * | 2013-09-10 | 2016-01-05 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD759068S1 (en) * | 2013-09-23 | 2016-06-14 | Bally Gaming, Inc. | Display screen or portion thereof with a baccarat game graphical user interface |
US20150147339A1 (en) | 2013-11-15 | 2015-05-28 | Psma Development Company, Llc | Biomarkers for psma targeted therapy for prostate cancer |
US20150205509A1 (en) * | 2013-12-02 | 2015-07-23 | Daydials, Inc. | User interface using graphical dials to represent user activity |
CA2930925A1 (en) * | 2014-02-06 | 2015-08-13 | Immunexpress Pty Ltd | Biomarker signature method, and apparatus and kits therefor |
GB201409479D0 (en) * | 2014-05-28 | 2014-07-09 | Almac Diagnostics Ltd | Molecular diagnostic test for cancer |
USD771063S1 (en) * | 2014-02-21 | 2016-11-08 | Huawei Device Co., Ltd. | Display screen or portion thereof with animated graphical user interface |
US20150254433A1 (en) * | 2014-03-05 | 2015-09-10 | Bruce MACHER | Methods and Models for Determining Likelihood of Cancer Drug Treatment Success Utilizing Predictor Biomarkers, and Methods of Diagnosing and Treating Cancer Using the Biomarkers |
USD711420S1 (en) * | 2014-03-14 | 2014-08-19 | Nike, Inc. | Display screen with graphical user interface for athletic achievements |
USD772241S1 (en) * | 2014-03-19 | 2016-11-22 | Symantec Corporation | Display screen or portion thereof with transitional graphical user interface |
USD759076S1 (en) * | 2014-04-18 | 2016-06-14 | Nutonian, Inc. | Display screen with graphical user interface |
US20150317430A1 (en) * | 2014-05-05 | 2015-11-05 | Advaita Corporation | Systems and methods for analyzing biological pathways for the purpose of modeling drug effects, side effects, and interactions |
FR3021776A1 (en) | 2014-05-28 | 2015-12-04 | Vaiomer | METHOD FOR IDENTIFYING A RELATION BETWEEN PHYSICAL ELEMENTS |
EP3936145A1 (en) * | 2014-07-31 | 2022-01-12 | The University Of Western Australia | A method for the identification of immunotherapy-drug combinations using a network approach |
USD762691S1 (en) * | 2014-09-01 | 2016-08-02 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD753696S1 (en) * | 2014-09-01 | 2016-04-12 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD765114S1 (en) * | 2014-09-02 | 2016-08-30 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD766950S1 (en) * | 2014-09-02 | 2016-09-20 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD757079S1 (en) * | 2014-09-02 | 2016-05-24 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD765693S1 (en) * | 2014-09-02 | 2016-09-06 | Apple Inc. | Display screen or portion thereof with graphical user interface |
CN107109459A (en) | 2014-11-05 | 2017-08-29 | 加利福尼亚大学董事会 | For the method for the non-responder for being layered the therapy to blocking PD1/PDL1 axles |
JP2018503373A (en) * | 2014-12-30 | 2018-02-08 | ジェネンテック, インコーポレイテッド | Methods and compositions for cancer prognosis and treatment |
USD765673S1 (en) * | 2014-12-30 | 2016-09-06 | Energous Corporation | Display screen with graphical user interface |
USD784402S1 (en) * | 2015-02-04 | 2017-04-18 | Sengled Optoelectronics Co., Ltd | Display screen with animated graphical user interface |
USD775185S1 (en) * | 2015-03-06 | 2016-12-27 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD765098S1 (en) * | 2015-03-06 | 2016-08-30 | Apple Inc. | Display screen or portion thereof with graphical user interface |
US20190057182A1 (en) * | 2015-05-22 | 2019-02-21 | Csts Health Care Inc. | Biomarker-driven molecularly targeted combination therapies based on knowledge representation pathway analysis |
US20180107783A1 (en) | 2015-05-28 | 2018-04-19 | Immunexpress Pty Ltd | Validating biomarker measurement |
WO2017004153A1 (en) * | 2015-06-29 | 2017-01-05 | The Broad Institute Inc. | Tumor and microenvironment gene expression, compositions of matter and methods of use thereof |
GB201512869D0 (en) | 2015-07-21 | 2015-09-02 | Almac Diagnostics Ltd | Gene signature for minute therapies |
AU2016305473B2 (en) * | 2015-08-13 | 2021-08-19 | Dana-Farber Cancer Institute, Inc. | Biomaterials for combined radiotherapy and immunotherapy of cancer |
JP6830105B2 (en) * | 2015-09-29 | 2021-02-17 | クレッシェンド バイオサイエンス インコーポレイテッド | Biomarkers and methods for assessing disease activity in psoriatic arthritis |
WO2017058999A2 (en) * | 2015-09-29 | 2017-04-06 | Crescendo Bioscience | Biomarkers and methods for assessing response to inflammatory disease therapy withdrawal |
USD809535S1 (en) * | 2015-10-06 | 2018-02-06 | Lg Electronics Inc. | Vehicle dashboard display screen with an animated graphical user interface |
USD855629S1 (en) * | 2015-10-23 | 2019-08-06 | Sony Corporation | Display panel or screen or portion thereof with an animated graphical user interface |
USD783656S1 (en) * | 2015-10-28 | 2017-04-11 | SynerScope B.V. | Display screen with graphical user interface |
USD795922S1 (en) * | 2015-11-05 | 2017-08-29 | Samsung Electronics Co., Ltd. | Display screen or portion thereof with animated graphical user interface |
USD797124S1 (en) * | 2015-11-18 | 2017-09-12 | Samsung Electronics Co., Ltd. | Display screen or portion thereof with graphical user interface |
GB201521481D0 (en) | 2015-12-04 | 2016-01-20 | Healx Ltd | Prognostic system |
USD799516S1 (en) * | 2015-12-23 | 2017-10-10 | Samsung Electronics Co., Ltd. | Display screen or portion thereof with graphical user interface |
USD806730S1 (en) * | 2016-01-05 | 2018-01-02 | Kneevoice, Inc. | Display screen or portion thereof with graphical user interface |
USD782516S1 (en) * | 2016-01-19 | 2017-03-28 | Apple Inc. | Display screen or portion thereof with graphical user interface |
CA169252S (en) * | 2016-02-04 | 2018-07-24 | Coway Co Ltd | Display screen with animated graphical user interface |
USD810757S1 (en) * | 2016-02-19 | 2018-02-20 | Samsung Electronics Co., Ltd. | Display screen or portion thereof with transitional graphical user interface |
JP1572940S (en) * | 2016-03-16 | 2018-06-18 | ||
USD807913S1 (en) * | 2016-03-17 | 2018-01-16 | Lg Electronics Inc. | Display panel with transitional graphical user interface |
USD802611S1 (en) * | 2016-04-14 | 2017-11-14 | Alpha Dominche Holdings, Inc. | Beverage brewer display screen with graphical user interface |
ES2808004T3 (en) | 2016-05-09 | 2021-02-25 | Inst Nat Sante Rech Med | Methods for Classifying Patients with Solid Cancer |
USD804502S1 (en) * | 2016-06-11 | 2017-12-05 | Apple Inc. | Display screen or portion thereof with graphical user interface |
USD835121S1 (en) * | 2016-06-15 | 2018-12-04 | Sony Interactive Entertainment Europe Limited | Display screen or portion thereof with graphical user interface |
USD882583S1 (en) * | 2016-07-12 | 2020-04-28 | Google Llc | Display screen with graphical user interface |
USD840413S1 (en) * | 2016-08-15 | 2019-02-12 | Facebook, Inc. | Display screen or portion thereof with digital visual codes graphical user interface |
USD852209S1 (en) * | 2016-08-24 | 2019-06-25 | Beijing Kingsoft Internet Security Software Co., Ltd. | Mobile communication terminal with animated graphical user interface |
USD813250S1 (en) * | 2016-08-30 | 2018-03-20 | Ponsse Oyj | Display screen with graphical user interface |
US11515008B2 (en) * | 2016-10-07 | 2022-11-29 | Omniseq, Inc. | Methods and systems for determining personalized t'herapies |
USD847857S1 (en) * | 2016-10-31 | 2019-05-07 | Agile Transformation, Inc. | Display screen or portion thereof with icon |
USD806120S1 (en) * | 2016-10-31 | 2017-12-26 | Agile Transformation, Inc. | Display screen or portion thereof with icon |
USD829730S1 (en) * | 2016-11-10 | 2018-10-02 | Karma Automotive Llc | Display screen with an infotainment graphical user interface |
USD865776S1 (en) * | 2016-11-18 | 2019-11-05 | Luis Miguel Porturas | Display screen with graphical user interface |
USD813249S1 (en) * | 2017-02-22 | 2018-03-20 | Banuba Limited | Display screen with an animated graphical user interface |
USD832283S1 (en) * | 2017-03-28 | 2018-10-30 | Akamai Technologies, Inc. | Display screen with animated graphical user interface |
USD822705S1 (en) * | 2017-04-20 | 2018-07-10 | Palantir Technologies, Inc. | Display screen or portion thereof with graphical user interface |
USD880489S1 (en) * | 2017-05-18 | 2020-04-07 | The Coca-Cola Company | Beverage dispenser display screen or portion thereof with animated graphical user interface |
USD818494S1 (en) * | 2017-06-04 | 2018-05-22 | Apple Inc. | Display screen or portion thereof with animated graphical user interface |
USD822059S1 (en) * | 2017-06-05 | 2018-07-03 | Apple Inc. | Display screen or portion thereof with graphical user interface |
GB2577828A (en) | 2017-06-13 | 2020-04-08 | Bostongene Corp | Systems and methods for identifying cancer treatments from normalized biomarker scores |
USD879808S1 (en) * | 2017-06-20 | 2020-03-31 | Ethicon Llc | Display panel with graphical user interface |
US20200377956A1 (en) | 2017-08-07 | 2020-12-03 | The Johns Hopkins University | Methods and materials for assessing and treating cancer |
USD833471S1 (en) * | 2017-08-18 | 2018-11-13 | Salesforce.Com, Inc. | Display screen or portion thereof with animated graphical user interface |
USD846585S1 (en) * | 2017-08-22 | 2019-04-23 | Samsung Electronics Co., Ltd. | Display screen or portion thereof with graphical user interface |
USD840415S1 (en) * | 2017-08-25 | 2019-02-12 | Samsung Electronics Co., Ltd. | Display screen or portion thereof with transitional graphical user interface |
USD860228S1 (en) * | 2017-09-05 | 2019-09-17 | Byton Limited | Display screen with a graphical user interface |
USD868103S1 (en) * | 2017-09-27 | 2019-11-26 | Toyota Research Institute, Inc. | Display screen or portion thereof with an animated graphical user interface |
EP3695408A4 (en) * | 2017-10-02 | 2021-12-15 | The Broad Institute, Inc. | Methods and compositions for detecting and modulating an immunotherapy resistance gene signature in cancer |
USD861022S1 (en) * | 2017-10-13 | 2019-09-24 | Honeywell International Inc. | Display screen or portion thereof with a graphical user interface |
USD879112S1 (en) * | 2017-11-14 | 2020-03-24 | Geographic Services, Inc. | Display screen or portion thereof with graphical user interface |
USD873854S1 (en) * | 2017-11-24 | 2020-01-28 | Fujifilm Corporation | Display screen or portion thereof with transitional icon |
USD870763S1 (en) * | 2018-01-05 | 2019-12-24 | Samsung Electronics Co., Ltd. | Display screen or portion thereof with graphical user interface |
USD852820S1 (en) * | 2018-01-19 | 2019-07-02 | Mouth Player Inc. | Display screen or portion thereof with animated graphical user interface |
USD878393S1 (en) * | 2018-01-30 | 2020-03-17 | Magic Leap, Inc. | Display panel or portion thereof with a transitional mixed reality graphical user interface |
USD868812S1 (en) * | 2018-02-16 | 2019-12-03 | Early Warning Services, Llc | Display screen portion with animated graphical user interface for transmittal notification |
USD868811S1 (en) * | 2018-02-22 | 2019-12-03 | Samsung Electronics Co., Ltd. | Display screen or portion thereof with transitional graphical user interface |
USD874482S1 (en) * | 2018-02-28 | 2020-02-04 | Fujifilm Corporation | Display screen or portion thereof with icon |
USD865807S1 (en) * | 2018-07-24 | 2019-11-05 | Magic Leap, Inc. | Display panel or portion thereof with a graphical user interface |
USD877176S1 (en) * | 2018-07-24 | 2020-03-03 | Magic Leap, Inc. | Display panel or portion thereof with a transitional graphical user interface |
USD879147S1 (en) * | 2018-07-31 | 2020-03-24 | Google Llc | Display screen with animated icon |
USD868094S1 (en) * | 2018-08-30 | 2019-11-26 | Apple Inc. | Electronic device with graphical user interface |
USD882615S1 (en) * | 2018-09-06 | 2020-04-28 | Apple Inc. | Electronic device with animated graphical user interface |
USD855073S1 (en) * | 2019-04-05 | 2019-07-30 | Le-Vel Brands, Llc | Display screen with icon |
-
2018
- 2018-06-12 GB GB1918389.6A patent/GB2577828A/en not_active Withdrawn
- 2018-06-12 US US16/006,572 patent/US10650911B2/en active Active
- 2018-06-12 SG SG10201911680SA patent/SG10201911680SA/en unknown
- 2018-06-12 US US16/006,381 patent/US20180358125A1/en not_active Abandoned
- 2018-06-12 US US16/006,462 patent/US11367509B2/en active Active
- 2018-06-12 EP EP21165384.5A patent/EP3879535A1/en active Pending
- 2018-06-12 US US16/006,555 patent/US10311967B2/en active Active
- 2018-06-12 CA CA3066004A patent/CA3066004A1/en active Pending
- 2018-06-12 EP EP22155044.5A patent/EP4012713A1/en active Pending
- 2018-06-12 US US16/006,279 patent/US10340030B2/en active Active
- 2018-06-12 CN CN201880046706.8A patent/CN111052247A/en active Pending
- 2018-06-12 AU AU2018102201A patent/AU2018102201A4/en active Active
- 2018-06-12 US US16/006,340 patent/US10340031B2/en active Active
- 2018-06-12 SG SG10201911541YA patent/SG10201911541YA/en unknown
- 2018-06-12 GB GB2201288.4A patent/GB2601923B8/en active Active
- 2018-06-12 AU AU2018284077A patent/AU2018284077B2/en active Active
- 2018-06-12 EP EP18735154.9A patent/EP3639172B1/en active Active
- 2018-06-12 JP JP2019569315A patent/JP6812580B2/en active Active
- 2018-06-12 CA CA3065193A patent/CA3065193A1/en active Pending
- 2018-06-12 US US16/006,200 patent/US20180358132A1/en not_active Abandoned
- 2018-06-12 JP JP2019569317A patent/JP6776464B2/en active Active
- 2018-06-12 KR KR1020207000663A patent/KR102396784B1/en active IP Right Grant
- 2018-06-12 WO PCT/US2018/037018 patent/WO2018231772A1/en unknown
- 2018-06-12 GB GB1918335.9A patent/GB2576680B/en active Active
- 2018-06-12 US US16/006,593 patent/US11322226B2/en active Active
- 2018-06-12 DE DE112018002990.5T patent/DE112018002990T5/en active Pending
- 2018-06-12 EP EP18738407.8A patent/EP3639170B1/en active Active
- 2018-06-12 GB GBGB2209539.2A patent/GB202209539D0/en not_active Ceased
- 2018-06-12 GB GB1918035.5A patent/GB2576857B/en active Active
- 2018-06-12 US US16/006,481 patent/US20200175134A9/en active Pending
- 2018-06-12 US US16/006,518 patent/US11430545B2/en active Active
- 2018-06-12 WO PCT/US2018/037017 patent/WO2018231771A1/en unknown
- 2018-06-12 EP EP18735155.6A patent/EP3639169B1/en active Active
- 2018-06-12 US US16/006,085 patent/US20180357361A1/en not_active Abandoned
- 2018-06-12 CA CA3065568A patent/CA3065568A1/en active Pending
- 2018-06-12 AU AU2018282865A patent/AU2018282865A1/en active Pending
- 2018-06-12 CN CN201880052383.3A patent/CN111033631B/en active Active
- 2018-06-12 WO PCT/US2018/037008 patent/WO2018231762A1/en unknown
- 2018-06-12 AU AU2018282759A patent/AU2018282759A1/en active Pending
- 2018-06-12 JP JP2019569239A patent/JP7034183B2/en active Active
- 2018-06-12 US US16/006,129 patent/US10720230B2/en active Active
-
2019
- 2019-04-22 US US16/391,221 patent/US10395761B1/en active Active
- 2019-06-10 US US29/694,308 patent/USD891446S1/en active Active
- 2019-06-10 US US29/694,310 patent/USD890779S1/en active Active
- 2019-06-28 US US16/456,462 patent/US11842797B2/en active Active
- 2019-06-28 US US16/456,370 patent/US10504615B2/en active Active
- 2019-07-26 US US16/523,808 patent/US10580517B2/en active Active
- 2019-10-24 US US16/662,280 patent/US10636513B2/en active Active
- 2019-11-06 US US16/676,375 patent/US10636514B2/en active Active
- 2019-11-25 IL IL270888A patent/IL270888A/en unknown
- 2019-11-25 IL IL270886A patent/IL270886A/en unknown
- 2019-11-25 IL IL270887A patent/IL270887A/en unknown
- 2019-11-26 US US16/696,128 patent/US10706954B2/en active Active
-
2020
- 2020-04-23 US US16/856,566 patent/US11004542B2/en active Active
- 2020-05-11 US US16/871,755 patent/US11302420B2/en active Active
- 2020-07-02 US US16/920,226 patent/US11373733B2/en active Active
- 2020-10-07 JP JP2020169806A patent/JP6999771B2/en active Active
- 2020-12-16 JP JP2020208441A patent/JP7408534B2/en active Active
-
2021
- 2021-04-22 US US17/237,672 patent/US11705220B2/en active Active
- 2021-12-21 JP JP2021207221A patent/JP7343565B2/en active Active
-
2022
- 2022-03-18 US US17/699,018 patent/US20220389512A1/en active Pending
-
2023
- 2023-08-31 JP JP2023140795A patent/JP7401710B2/en active Active
- 2023-09-01 US US18/460,330 patent/US20240006029A1/en active Pending
- 2023-12-20 JP JP2023214362A patent/JP2024029038A/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11705220B2 (en) | Systems and methods for identifying cancer treatments from normalized biomarker scores |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |