JP2016508519A - 新規のegfr変異体 - Google Patents
新規のegfr変異体 Download PDFInfo
- Publication number
- JP2016508519A JP2016508519A JP2015558160A JP2015558160A JP2016508519A JP 2016508519 A JP2016508519 A JP 2016508519A JP 2015558160 A JP2015558160 A JP 2015558160A JP 2015558160 A JP2015558160 A JP 2015558160A JP 2016508519 A JP2016508519 A JP 2016508519A
- Authority
- JP
- Japan
- Prior art keywords
- egfr
- cancer
- protein
- egfrvvi
- subject
- 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.)
- Granted
Links
- 102000052116 epidermal growth factor receptor activity proteins Human genes 0.000 title abstract 4
- 108700015053 epidermal growth factor receptor activity proteins Proteins 0.000 title abstract 4
- 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 title abstract 4
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 95
- 238000000034 method Methods 0.000 claims abstract description 71
- 102000001301 EGF receptor Human genes 0.000 claims description 208
- 108060006698 EGF receptor Proteins 0.000 claims description 207
- 201000011510 cancer Diseases 0.000 claims description 63
- 125000003729 nucleotide group Chemical group 0.000 claims description 29
- 239000002773 nucleotide Substances 0.000 claims description 28
- 238000011282 treatment Methods 0.000 claims description 28
- 208000005017 glioblastoma Diseases 0.000 claims description 26
- 238000012217 deletion Methods 0.000 claims description 25
- 230000037430 deletion Effects 0.000 claims description 25
- 108090000623 proteins and genes Proteins 0.000 claims description 21
- 102000004169 proteins and genes Human genes 0.000 claims description 20
- 201000010915 Glioblastoma multiforme Diseases 0.000 claims description 17
- 239000012472 biological sample Substances 0.000 claims description 17
- 108091033319 polynucleotide Proteins 0.000 claims description 17
- 102000040430 polynucleotide Human genes 0.000 claims description 17
- 239000002157 polynucleotide Substances 0.000 claims description 17
- 150000001413 amino acids Chemical class 0.000 claims description 15
- 239000003112 inhibitor Substances 0.000 claims description 14
- 229940121647 egfr inhibitor Drugs 0.000 claims description 12
- 230000014509 gene expression Effects 0.000 claims description 11
- 239000003814 drug Substances 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 9
- 230000004043 responsiveness Effects 0.000 claims description 8
- 150000003384 small molecules Chemical group 0.000 claims description 8
- 208000026310 Breast neoplasm Diseases 0.000 claims description 6
- 201000009030 Carcinoma Diseases 0.000 claims description 6
- 206010058467 Lung neoplasm malignant Diseases 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 6
- 230000009368 gene silencing by RNA Effects 0.000 claims description 6
- 201000005202 lung cancer Diseases 0.000 claims description 6
- 208000020816 lung neoplasm Diseases 0.000 claims description 6
- 206010006187 Breast cancer Diseases 0.000 claims description 5
- 206010060862 Prostate cancer Diseases 0.000 claims description 5
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 5
- -1 antibody Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 208000029742 colonic neoplasm Diseases 0.000 claims description 5
- 210000000653 nervous system Anatomy 0.000 claims description 5
- 206010009944 Colon cancer Diseases 0.000 claims description 4
- 239000002246 antineoplastic agent Substances 0.000 claims description 4
- 229940079593 drug Drugs 0.000 claims description 4
- 229940124597 therapeutic agent Drugs 0.000 claims description 4
- 229940127089 cytotoxic agent Drugs 0.000 claims description 3
- 238000011161 development Methods 0.000 claims description 3
- 201000011682 nervous system cancer Diseases 0.000 claims description 3
- 239000003053 toxin Substances 0.000 claims description 3
- 231100000765 toxin Toxicity 0.000 claims description 3
- 239000002105 nanoparticle Substances 0.000 claims description 2
- 230000008685 targeting Effects 0.000 claims description 2
- 108091030071 RNAI Proteins 0.000 claims 2
- 238000004393 prognosis Methods 0.000 abstract description 9
- 238000003745 diagnosis Methods 0.000 abstract description 8
- 230000001225 therapeutic effect Effects 0.000 abstract description 7
- 238000011156 evaluation Methods 0.000 abstract description 3
- 239000000523 sample Substances 0.000 description 50
- 150000007523 nucleic acids Chemical class 0.000 description 39
- 102000039446 nucleic acids Human genes 0.000 description 35
- 108020004707 nucleic acids Proteins 0.000 description 35
- 230000003321 amplification Effects 0.000 description 33
- 238000003199 nucleic acid amplification method Methods 0.000 description 33
- 108700024394 Exon Proteins 0.000 description 25
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 22
- 108020004414 DNA Proteins 0.000 description 20
- 210000004027 cell Anatomy 0.000 description 18
- 238000003752 polymerase chain reaction Methods 0.000 description 18
- 238000001514 detection method Methods 0.000 description 17
- 108010087914 epidermal growth factor receptor VIII Proteins 0.000 description 17
- 238000003556 assay Methods 0.000 description 14
- 230000000694 effects Effects 0.000 description 14
- 108020004635 Complementary DNA Proteins 0.000 description 13
- 125000003275 alpha amino acid group Chemical group 0.000 description 13
- 238000010804 cDNA synthesis Methods 0.000 description 12
- 210000001175 cerebrospinal fluid Anatomy 0.000 description 12
- 239000002299 complementary DNA Substances 0.000 description 12
- 108091034117 Oligonucleotide Proteins 0.000 description 10
- 206010003571 Astrocytoma Diseases 0.000 description 9
- 108091028043 Nucleic acid sequence Proteins 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 108020001756 ligand binding domains Proteins 0.000 description 9
- 238000002493 microarray Methods 0.000 description 9
- 238000012163 sequencing technique Methods 0.000 description 9
- 238000011529 RT qPCR Methods 0.000 description 8
- 230000000295 complement effect Effects 0.000 description 8
- 238000002405 diagnostic procedure Methods 0.000 description 8
- 239000000203 mixture Substances 0.000 description 8
- 230000010261 cell growth Effects 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 201000010099 disease Diseases 0.000 description 7
- 238000009396 hybridization Methods 0.000 description 7
- 238000011503 in vivo imaging Methods 0.000 description 7
- 108020004999 messenger RNA Proteins 0.000 description 7
- 230000035772 mutation Effects 0.000 description 7
- 230000019491 signal transduction Effects 0.000 description 7
- 102000001708 Protein Isoforms Human genes 0.000 description 6
- 108010029485 Protein Isoforms Proteins 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 230000001404 mediated effect Effects 0.000 description 6
- 239000013074 reference sample Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 210000001519 tissue Anatomy 0.000 description 6
- 210000004881 tumor cell Anatomy 0.000 description 6
- 108020004711 Nucleic Acid Probes Proteins 0.000 description 5
- 230000007783 downstream signaling Effects 0.000 description 5
- 239000000975 dye Substances 0.000 description 5
- 239000012634 fragment Substances 0.000 description 5
- 238000002372 labelling Methods 0.000 description 5
- 239000002853 nucleic acid probe Substances 0.000 description 5
- 230000035755 proliferation Effects 0.000 description 5
- 230000004083 survival effect Effects 0.000 description 5
- 238000011269 treatment regimen Methods 0.000 description 5
- 238000000018 DNA microarray Methods 0.000 description 4
- 239000005411 L01XE02 - Gefitinib Substances 0.000 description 4
- 239000005551 L01XE03 - Erlotinib Substances 0.000 description 4
- 239000002136 L01XE07 - Lapatinib Substances 0.000 description 4
- 206010027476 Metastases Diseases 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 4
- 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 4
- 210000001124 body fluid Anatomy 0.000 description 4
- 210000004899 c-terminal region Anatomy 0.000 description 4
- 230000004663 cell proliferation Effects 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 238000001962 electrophoresis Methods 0.000 description 4
- 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 4
- 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 4
- 239000003102 growth factor Substances 0.000 description 4
- 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 4
- 238000007834 ligase chain reaction Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 230000003211 malignant effect Effects 0.000 description 4
- 230000009401 metastasis Effects 0.000 description 4
- 229960001972 panitumumab Drugs 0.000 description 4
- 108090000765 processed proteins & peptides Chemical group 0.000 description 4
- 102000004196 processed proteins & peptides Human genes 0.000 description 4
- 230000002062 proliferating effect Effects 0.000 description 4
- 102000005962 receptors Human genes 0.000 description 4
- 108020003175 receptors Proteins 0.000 description 4
- 238000003757 reverse transcription PCR Methods 0.000 description 4
- 229960005560 rindopepimut Drugs 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- 206010008342 Cervix carcinoma Diseases 0.000 description 3
- 208000021994 Diffuse astrocytoma Diseases 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 102100031780 Endonuclease Human genes 0.000 description 3
- 206010061902 Pancreatic neoplasm Diseases 0.000 description 3
- 208000006265 Renal cell carcinoma Diseases 0.000 description 3
- 208000000102 Squamous Cell Carcinoma of Head and Neck Diseases 0.000 description 3
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 3
- 230000005856 abnormality Effects 0.000 description 3
- 238000000137 annealing Methods 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 238000001574 biopsy Methods 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 230000012292 cell migration Effects 0.000 description 3
- 201000010881 cervical cancer Diseases 0.000 description 3
- 238000006073 displacement reaction Methods 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 201000000459 head and neck squamous cell carcinoma Diseases 0.000 description 3
- 238000003018 immunoassay Methods 0.000 description 3
- 238000007901 in situ hybridization Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 208000015486 malignant pancreatic neoplasm Diseases 0.000 description 3
- 239000003550 marker Substances 0.000 description 3
- 201000001441 melanoma Diseases 0.000 description 3
- 206010027191 meningioma Diseases 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 201000002528 pancreatic cancer Diseases 0.000 description 3
- 208000008443 pancreatic carcinoma Diseases 0.000 description 3
- 229920001184 polypeptide Chemical group 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 239000000439 tumor marker Substances 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- NMWKYTGJWUAZPZ-WWHBDHEGSA-N (4S)-4-[[(4R,7S,10S,16S,19S,25S,28S,31R)-31-[[(2S)-2-[[(1R,6R,9S,12S,18S,21S,24S,27S,30S,33S,36S,39S,42R,47R,53S,56S,59S,62S,65S,68S,71S,76S,79S,85S)-47-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-4-yl)propanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]-3-carboxypropanoyl]amino]-18-(4-aminobutyl)-27,68-bis(3-amino-3-oxopropyl)-36,71,76-tribenzyl-39-(3-carbamimidamidopropyl)-24-(2-carboxyethyl)-21,56-bis(carboxymethyl)-65,85-bis[(1R)-1-hydroxyethyl]-59-(hydroxymethyl)-62,79-bis(1H-imidazol-4-ylmethyl)-9-methyl-33-(2-methylpropyl)-8,11,17,20,23,26,29,32,35,38,41,48,54,57,60,63,66,69,72,74,77,80,83,86-tetracosaoxo-30-propan-2-yl-3,4,44,45-tetrathia-7,10,16,19,22,25,28,31,34,37,40,49,55,58,61,64,67,70,73,75,78,81,84,87-tetracosazatetracyclo[40.31.14.012,16.049,53]heptaoctacontane-6-carbonyl]amino]-3-methylbutanoyl]amino]-7-(3-carbamimidamidopropyl)-25-(hydroxymethyl)-19-[(4-hydroxyphenyl)methyl]-28-(1H-imidazol-4-ylmethyl)-10-methyl-6,9,12,15,18,21,24,27,30-nonaoxo-16-propan-2-yl-1,2-dithia-5,8,11,14,17,20,23,26,29-nonazacyclodotriacontane-4-carbonyl]amino]-5-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-imidazol-4-yl)-1-oxopropan-2-yl]amino]-5-oxopentanoic acid Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H]1CSSC[C@H](NC(=O)[C@@H](NC(=O)[C@@H]2CSSC[C@@H]3NC(=O)[C@H](Cc4ccccc4)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H]4CCCN4C(=O)[C@H](CSSC[C@H](NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](Cc4c[nH]cn4)NC(=O)[C@H](Cc4ccccc4)NC3=O)[C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc3ccccc3)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N3CCC[C@H]3C(=O)N[C@@H](C)C(=O)N2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2c[nH]cn2)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)C(C)C)C(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](Cc2ccc(O)cc2)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1)C(=O)N[C@@H](C)C(O)=O NMWKYTGJWUAZPZ-WWHBDHEGSA-N 0.000 description 2
- HRYKZAKEAVZGJD-UHFFFAOYSA-N 2-methyl-3,5,7,8-tetrahydro-4h-thiopyrano[4,3-d]pyrimidin-4-one Chemical compound C1CSCC2=C1N=C(C)NC2=O HRYKZAKEAVZGJD-UHFFFAOYSA-N 0.000 description 2
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 2
- 101800001382 Betacellulin Proteins 0.000 description 2
- 206010005003 Bladder cancer Diseases 0.000 description 2
- 208000005443 Circulating Neoplastic Cells Diseases 0.000 description 2
- 108091026890 Coding region Proteins 0.000 description 2
- 230000006820 DNA synthesis Effects 0.000 description 2
- 101150039808 Egfr gene Proteins 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 101800003838 Epidermal growth factor Proteins 0.000 description 2
- 101800000155 Epiregulin Proteins 0.000 description 2
- 102000009465 Growth Factor Receptors Human genes 0.000 description 2
- 108010009202 Growth Factor Receptors Proteins 0.000 description 2
- 101800001649 Heparin-binding EGF-like growth factor Proteins 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 238000000636 Northern blotting Methods 0.000 description 2
- 108010064218 Poly (ADP-Ribose) Polymerase-1 Proteins 0.000 description 2
- 102100023712 Poly [ADP-ribose] polymerase 1 Human genes 0.000 description 2
- 102100033237 Pro-epidermal growth factor Human genes 0.000 description 2
- 102100029837 Probetacellulin Human genes 0.000 description 2
- 102100025498 Proepiregulin Human genes 0.000 description 2
- 102100033762 Proheparin-binding EGF-like growth factor Human genes 0.000 description 2
- 102100032350 Protransforming growth factor alpha Human genes 0.000 description 2
- 239000003391 RNA probe Substances 0.000 description 2
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 2
- 101710100969 Receptor tyrosine-protein kinase erbB-3 Proteins 0.000 description 2
- 101710100963 Receptor tyrosine-protein kinase erbB-4 Proteins 0.000 description 2
- 238000002105 Southern blotting Methods 0.000 description 2
- 101800004564 Transforming growth factor alpha Proteins 0.000 description 2
- 208000007097 Urinary Bladder Neoplasms Diseases 0.000 description 2
- 230000000692 anti-sense effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000008827 biological function Effects 0.000 description 2
- 239000000090 biomarker Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 229940022399 cancer vaccine Drugs 0.000 description 2
- 238000009566 cancer vaccine Methods 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 229960005395 cetuximab Drugs 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000002038 chemiluminescence detection Methods 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000002591 computed tomography Methods 0.000 description 2
- 230000007423 decrease Effects 0.000 description 2
- 238000004925 denaturation Methods 0.000 description 2
- 230000036425 denaturation Effects 0.000 description 2
- 208000035475 disorder Diseases 0.000 description 2
- 230000003511 endothelial effect Effects 0.000 description 2
- 229940116977 epidermal growth factor Drugs 0.000 description 2
- 108700021358 erbB-1 Genes Proteins 0.000 description 2
- 229940082789 erbitux Drugs 0.000 description 2
- 229960001433 erlotinib Drugs 0.000 description 2
- 238000001917 fluorescence detection Methods 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000002509 fluorescent in situ hybridization Methods 0.000 description 2
- 108020001507 fusion proteins Proteins 0.000 description 2
- 102000037865 fusion proteins Human genes 0.000 description 2
- 229960002584 gefitinib Drugs 0.000 description 2
- 230000003463 hyperproliferative effect Effects 0.000 description 2
- 238000003384 imaging method Methods 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 229940084651 iressa Drugs 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229960004891 lapatinib Drugs 0.000 description 2
- 238000002595 magnetic resonance imaging Methods 0.000 description 2
- 230000036210 malignancy Effects 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- 238000010369 molecular cloning Methods 0.000 description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 description 2
- 238000007899 nucleic acid hybridization Methods 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 210000002381 plasma Anatomy 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 238000002600 positron emission tomography Methods 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 238000000734 protein sequencing Methods 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- 238000000163 radioactive labelling Methods 0.000 description 2
- 208000015347 renal cell adenocarcinoma Diseases 0.000 description 2
- 238000010839 reverse transcription Methods 0.000 description 2
- 210000003296 saliva Anatomy 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 238000011895 specific detection Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229940120982 tarceva Drugs 0.000 description 2
- 229940094060 tykerb Drugs 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 201000005112 urinary bladder cancer Diseases 0.000 description 2
- VBEQCZHXXJYVRD-GACYYNSASA-N uroanthelone Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)C(C)C)[C@@H](C)O)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CCSC)NC(=O)[C@H](CS)NC(=O)[C@@H](NC(=O)CNC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CS)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CS)NC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC(N)=O)C(C)C)[C@@H](C)CC)C1=CC=C(O)C=C1 VBEQCZHXXJYVRD-GACYYNSASA-N 0.000 description 2
- 102000040650 (ribonucleotides)n+m Human genes 0.000 description 1
- LQJVOLSLAFIXSV-UHFFFAOYSA-N 4h-thieno[2,3-c]isoquinolin-5-one Chemical compound C12=CC=CC=C2C(=O)NC2=C1C=CS2 LQJVOLSLAFIXSV-UHFFFAOYSA-N 0.000 description 1
- KWNLARCFSYAXLT-UHFFFAOYSA-N 5-amino-2h-isoquinolin-1-one;hydrochloride Chemical compound Cl.C1=CNC(=O)C2=C1C(N)=CC=C2 KWNLARCFSYAXLT-UHFFFAOYSA-N 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000936 Agarose Polymers 0.000 description 1
- 102100038778 Amphiregulin Human genes 0.000 description 1
- 108010033760 Amphiregulin Proteins 0.000 description 1
- 108091093088 Amplicon Proteins 0.000 description 1
- 101100067974 Arabidopsis thaliana POP2 gene Proteins 0.000 description 1
- 206010003445 Ascites Diseases 0.000 description 1
- 241000283690 Bos taurus Species 0.000 description 1
- 241000700199 Cavia porcellus Species 0.000 description 1
- 108091033380 Coding strand Proteins 0.000 description 1
- 102000012410 DNA Ligases Human genes 0.000 description 1
- 108010061982 DNA Ligases Proteins 0.000 description 1
- 239000003298 DNA probe Substances 0.000 description 1
- 108010014303 DNA-directed DNA polymerase Proteins 0.000 description 1
- 102000016928 DNA-directed DNA polymerase Human genes 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- 101150029707 ERBB2 gene Proteins 0.000 description 1
- 108010042407 Endonucleases Proteins 0.000 description 1
- 102100030323 Epigen Human genes 0.000 description 1
- 108010016906 Epigen Proteins 0.000 description 1
- 241000283073 Equus caballus Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010061968 Gastric neoplasm Diseases 0.000 description 1
- 208000032612 Glial tumor Diseases 0.000 description 1
- 206010018338 Glioma Diseases 0.000 description 1
- 206010019695 Hepatic neoplasm Diseases 0.000 description 1
- 101100118549 Homo sapiens EGFR gene Proteins 0.000 description 1
- 101000851181 Homo sapiens Epidermal growth factor receptor Proteins 0.000 description 1
- 101001012157 Homo sapiens Receptor tyrosine-protein kinase erbB-2 Proteins 0.000 description 1
- 102000001706 Immunoglobulin Fab Fragments Human genes 0.000 description 1
- 108010054477 Immunoglobulin Fab Fragments Proteins 0.000 description 1
- 102000008394 Immunoglobulin Fragments Human genes 0.000 description 1
- 108010021625 Immunoglobulin Fragments Proteins 0.000 description 1
- 208000008839 Kidney Neoplasms Diseases 0.000 description 1
- 239000002118 L01XE12 - Vandetanib Substances 0.000 description 1
- 102000043136 MAP kinase family Human genes 0.000 description 1
- 108091054455 MAP kinase family Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 102000012750 Membrane Glycoproteins Human genes 0.000 description 1
- 108010090054 Membrane Glycoproteins Proteins 0.000 description 1
- 108700019961 Neoplasm Genes Proteins 0.000 description 1
- 102000048850 Neoplasm Genes Human genes 0.000 description 1
- 206010061309 Neoplasm progression Diseases 0.000 description 1
- 206010029098 Neoplasm skin Diseases 0.000 description 1
- 101710163270 Nuclease Proteins 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 108700020796 Oncogene Proteins 0.000 description 1
- 102000043276 Oncogene Human genes 0.000 description 1
- 206010061535 Ovarian neoplasm Diseases 0.000 description 1
- 239000012661 PARP inhibitor Substances 0.000 description 1
- 108091033411 PCA3 Proteins 0.000 description 1
- 238000002944 PCR assay Methods 0.000 description 1
- 108010043958 Peptoids Proteins 0.000 description 1
- 241000009328 Perro Species 0.000 description 1
- 108091000080 Phosphotransferase Proteins 0.000 description 1
- 241000276498 Pollachius virens Species 0.000 description 1
- 229940121906 Poly ADP ribose polymerase inhibitor Drugs 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 108020004518 RNA Probes Proteins 0.000 description 1
- 239000013614 RNA sample Substances 0.000 description 1
- 208000037323 Rare tumor Diseases 0.000 description 1
- 102100030086 Receptor tyrosine-protein kinase erbB-2 Human genes 0.000 description 1
- 102100029986 Receptor tyrosine-protein kinase erbB-3 Human genes 0.000 description 1
- 102100029981 Receptor tyrosine-protein kinase erbB-4 Human genes 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- 102000014400 SH2 domains Human genes 0.000 description 1
- 108050003452 SH2 domains Proteins 0.000 description 1
- 101100123851 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HER1 gene Proteins 0.000 description 1
- 229920002684 Sepharose Polymers 0.000 description 1
- 238000012300 Sequence Analysis Methods 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 208000000453 Skin Neoplasms Diseases 0.000 description 1
- 108020004459 Small interfering RNA Proteins 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 238000011256 aggressive treatment Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 210000004381 amniotic fluid Anatomy 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 206010002224 anaplastic astrocytoma Diseases 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 238000011394 anticancer treatment Methods 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 210000001130 astrocyte Anatomy 0.000 description 1
- 230000035578 autophosphorylation Effects 0.000 description 1
- 239000011324 bead Substances 0.000 description 1
- 239000013060 biological fluid Substances 0.000 description 1
- 239000012620 biological material Substances 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- 238000007707 calorimetry Methods 0.000 description 1
- 230000009702 cancer cell proliferation Effects 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000021164 cell adhesion Effects 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- 230000005779 cell damage Effects 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000032823 cell division Effects 0.000 description 1
- 208000037887 cell injury Diseases 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 230000009134 cell regulation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 150000005829 chemical entities Chemical class 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 230000008711 chromosomal rearrangement Effects 0.000 description 1
- 239000013068 control sample Substances 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 210000002726 cyst fluid Anatomy 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 239000002254 cytotoxic agent Substances 0.000 description 1
- 231100000599 cytotoxic agent Toxicity 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 230000003831 deregulation Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 238000007878 drug screening assay Methods 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 210000001808 exosome Anatomy 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 201000001169 fibrillary astrocytoma Diseases 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000000684 flow cytometry Methods 0.000 description 1
- 238000001215 fluorescent labelling Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 239000000833 heterodimer Substances 0.000 description 1
- 239000000710 homodimer Substances 0.000 description 1
- 210000004251 human milk Anatomy 0.000 description 1
- 235000020256 human milk Nutrition 0.000 description 1
- 238000003312 immunocapture Methods 0.000 description 1
- 230000000984 immunochemical effect Effects 0.000 description 1
- 238000003365 immunocytochemistry Methods 0.000 description 1
- 238000011532 immunohistochemical staining Methods 0.000 description 1
- 238000003364 immunohistochemistry Methods 0.000 description 1
- 238000001114 immunoprecipitation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000004255 ion exchange chromatography Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000004816 latex Substances 0.000 description 1
- 229920000126 latex Polymers 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 208000014018 liver neoplasm Diseases 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 208000037841 lung tumor Diseases 0.000 description 1
- 210000004880 lymph fluid Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 229950008001 matuzumab Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000037819 metastatic cancer Diseases 0.000 description 1
- 208000011575 metastatic malignant neoplasm Diseases 0.000 description 1
- MYWUZJCMWCOHBA-VIFPVBQESA-N methamphetamine Chemical compound CN[C@@H](C)CC1=CC=CC=C1 MYWUZJCMWCOHBA-VIFPVBQESA-N 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- DYKFCLLONBREIL-KVUCHLLUSA-N minocycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=CC(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O DYKFCLLONBREIL-KVUCHLLUSA-N 0.000 description 1
- 229960004023 minocycline Drugs 0.000 description 1
- 230000002297 mitogenic effect Effects 0.000 description 1
- 230000000394 mitotic effect Effects 0.000 description 1
- 238000009126 molecular therapy Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 208000017708 myomatous neoplasm Diseases 0.000 description 1
- 230000017074 necrotic cell death Effects 0.000 description 1
- 208000025402 neoplasm of esophagus Diseases 0.000 description 1
- 206010061311 nervous system neoplasm Diseases 0.000 description 1
- 229950010203 nimotuzumab Drugs 0.000 description 1
- 210000000019 nipple aspirate fluid Anatomy 0.000 description 1
- 210000004789 organ system Anatomy 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000816 peptidomimetic Substances 0.000 description 1
- 230000011340 peptidyl-tyrosine autophosphorylation Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 102000020233 phosphotransferase Human genes 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 210000004910 pleural fluid Anatomy 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 208000030266 primary brain neoplasm Diseases 0.000 description 1
- VYXXMAGSIYIYGD-NWAYQTQBSA-N propan-2-yl 2-[[[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(pyrimidine-4-carbonylamino)phosphoryl]amino]-2-methylpropanoate Chemical compound CC(C)OC(=O)C(C)(C)NP(=O)(CO[C@H](C)Cn1cnc2c(N)ncnc12)NC(=O)c1ccncn1 VYXXMAGSIYIYGD-NWAYQTQBSA-N 0.000 description 1
- 238000002331 protein detection Methods 0.000 description 1
- 238000000751 protein extraction Methods 0.000 description 1
- 230000004063 proteosomal degradation Effects 0.000 description 1
- 238000007859 qualitative PCR Methods 0.000 description 1
- 238000011158 quantitative evaluation Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 102000027426 receptor tyrosine kinases Human genes 0.000 description 1
- 108091008598 receptor tyrosine kinases Proteins 0.000 description 1
- 230000009703 regulation of cell differentiation Effects 0.000 description 1
- 230000031539 regulation of cell division Effects 0.000 description 1
- 230000025053 regulation of cell proliferation Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 108091008146 restriction endonucleases Proteins 0.000 description 1
- 238000010845 search algorithm Methods 0.000 description 1
- 210000000582 semen Anatomy 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 238000001542 size-exclusion chromatography Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 230000004936 stimulating effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000013517 stratification Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 239000000107 tumor biomarker Substances 0.000 description 1
- 208000025421 tumor of uterus Diseases 0.000 description 1
- 230000005751 tumor progression Effects 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 210000004291 uterus Anatomy 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
- 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
- 238000011179 visual inspection Methods 0.000 description 1
- 238000001262 western blot Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/475—Growth factors; Growth regulators
- C07K14/485—Epidermal growth factor [EGF], i.e. urogastrone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/71—Receptors; Cell surface antigens; Cell surface determinants for growth factors; for growth regulators
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
- C12N15/1138—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing against receptors or cell surface proteins
-
- 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
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
- G01N33/57492—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds localized on the membrane of tumor or cancer cells
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
- C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2310/00—Structure or type of the nucleic acid
- C12N2310/10—Type of nucleic acid
- C12N2310/14—Type of nucleic acid interfering N.A.
-
- 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
- C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
-
- 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
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/71—Assays involving receptors, cell surface antigens or cell surface determinants for growth factors; for growth regulators
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Immunology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- General Health & Medical Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Zoology (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Biophysics (AREA)
- Cell Biology (AREA)
- Biomedical Technology (AREA)
- Biotechnology (AREA)
- Wood Science & Technology (AREA)
- Oncology (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- Gastroenterology & Hepatology (AREA)
- Physics & Mathematics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Microbiology (AREA)
- General Engineering & Computer Science (AREA)
- Hospice & Palliative Care (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- Toxicology (AREA)
- Food Science & Technology (AREA)
- General Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Public Health (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Veterinary Medicine (AREA)
- Plant Pathology (AREA)
Abstract
Description
本願は、2013年2月15日に出願された米国特許仮出願第61/765,537号に対し、優先権の利益を主張し、その内容は、参照によりその全内容において本明細書に組み込まれている。
本発明は、膠芽腫患者において同定された新規のEGFR変異体の発見に基づく。本発明は、がんのより正確な診断及びがんの素因についてのがんバイオマーカー、並びにがんを治療するための治療計画を導くバイオマーカーの必要性に向けられる。一般に本発明は、本明細書においてEGFRvVIと称される新規のEGFR変異体を特徴とする。さらに本発明は、がんの診断、予後診断、及び/または治療指針のためのEGFR変異体の検出に関する。
本発明は、上皮成長因子受容体(EGFR)の新規の変異体の発見に基づく。EGFRの突然変異及び過剰発現は、肺がん、いくつかの上皮がん、及び多形性膠芽腫を含める多くのがんに関連していることが公知である。一般にがんにおいて見出されるEGFRvIII変異体等のEGFR突然変異は、EGFRの構造的な活性化を引き起こし、がんの顕著な特徴である非制御の細胞分裂を引き起こし得る下流のシグナル伝達をもたらす。結果として、EGFRの突然変異型の存在は、がんの存在、またはがんのより高い素因を示し得る。さらに近年の治療法は、EGFRを標的にするように、特にEGFR活性を阻害するように設計されてきた。特定のEGFR突然変異を伴うがん患者は、しばしば突然変異したドメインまたは領域の結合または阻害を介して作用するそれらの治療法に非応答性である。したがってEGFR突然変異体は、対象ががん、またはがんの高い素因を有するか否かを診断するために、並びにがん患者の特定の治療計画への応答性を決定するために、または治療計画の有効性を決定するために有用である。
上皮成長因子受容体(EGFR)は、細胞表面上に存在するErbB(HER及びヒト上皮成長因子受容体としても公知である)シグナル伝達経路における四つの受容体のうちの一つである。さらにEGFRは、ErbB−1及びHER1としても公知である。HERファミリーの他のメンバーは、ErbB−2(HER2/c−neu)、ErbB−3(HER3)、及びErbB−4(HER4)を含める。
GTCCGGGCAGCCCCCGGCGCAGCGCGGCCGCAGCAGCCTCCTCCCCCCGCACGGTGTGAGCGCCCGCCGCGGCCGAGGCGGCCGGAGTCCCGAGCTAGCCCCGGCGGCCGCCGCCGCCCAGACCGGACGACAGGCCACCTCGTCGGCGTCCGCCCGAGTCCCCGCCTCGCCGCCAACGCCACAACCACCGCGCACGGCCCCCTGACTCCGTCCAGTATTGATCGGGAGAGCCGGAGCGAGCTCTTCGGGGAGCAGCGATGCGACCCTCCGGGACGGCCGGGGCAGCGCTCCTGGCGCTGCTGGCTGCGCTCTGCCCGGCGAGTCGGGCTCTGGAGGAAAAGAAAGTTTGCCAAGGCACGAGTAACAAGCTCACGCAGTTGGGCACTTTTGAAGATCATTTTCTCAGCCTCCAGAGGATGTTCAATAACTGTGAGGTGGTCCTTGGGAATTTGGAAATTACCTATGTGCAGAGGAATTATGATCTTTCCTTCTTAAAGACCATCCAGGAGGTGGCTGGTTATGTCCTCATTGCCCTCAACACAGTGGAGCGAATTCCTTTGGAAAACCTGCAGATCATCAGAGGAAATATGTACTACGAAAATTCCTATGCCTTAGCAGTCTTATCTAACTATGATGCAAATAAAACCGGACTGAAGGAGCTGCCCATGAGAAATTTACAGGGACAAAAGTGTGATCCAAGCTGTCCCAATGGGAGCTGCTGGGGTGCAGGAGAGGAGAACTGCCAGAAACTGACCAAAATCATCTGTGCCCAGCAGTGCTCCGGGCGCTGCCGTGGCAAGTCCCCCAGTGACTGCTGCCACAACCAGTGTGCTGCAGGCTGCACAGGCCCCCGGGAGAGCGACTGCCTGGTCTGCCGCAAATTCCGAGACGAAGCCACGTGCAAGGACACCTGCCCCCCACTCATGCTCTACAACCCCACCACGTACCAGATGGATGTGAACCCCGAGGGCAAATACAGCTTTGGTGCCACCTGCGTGAAGAAGTGTCCCCGTAATTATGTGGTGACAGATCACGGCTCGTGCGTCCGAGCCTGTGGGGCCGACAGCTATGAGATGGAGGAAGACGGCGTCCGCAAGTGTAAGAAGTGCGAAGGGCCTTGCCGCAAAGTGTGTAACGGAATAGGTATTGGTGAATTTAAAGACTCACTCTCCATAAATGCTACGAATATTAAACACTTCAAAAACTGCACCTCCATCAGTGGCGATCTCCACATCCTGCCGGTGGCATTTAGGGGTGACTCCTTCACACATACTCCTCCTCTGGATCCACAGGAACTGGATATTCTGAAAACCGTAAAGGAAATCACAGGGTTTTTGCTGATTCAGGCTTGGCCTGAAAACAGGACGGACCTCCATGCCTTTGAGAACCTAGAAATCATACGCGGCAGGACCAAGCAACATGGTCAGTTTTCTCTTGCAGTCGTCAGCCTGAACATAACATCCTTGGGATTACGCTCCCTCAAGGAGATAAGTGATGGAGATGTGATAATTTCAGGAAACAAAAATTTGTGCTATGCAAATACAATAAACTGGAAAAAACTGTTTGGGACCTCCGGTCAGAAAACCAAAATTATAAGCAACAGAGGTGAAAACAGCTGCAAGGCCACAGGCCAGGTCTGCCATGCCTTGTGCTCCCCCGAGGGCTGCTGGGGCCCGGAGCCCAGGGACTGCGTCTCTTGCCGGAATGTCAGCCGAGGCAGGGAATGCGTGGACAAGTGCAACCTTCTGGAGGGTGAGCCAAGGGAGTTTGTGGAGAACTCTGAGTGCATACAGTGCCACCCAGAGTGCCTGCCTCAGGCCATGAACATCACCTGCACAGGACGGGGACCAGACAACTGTATCCAGTGTGCCCACTACATTGACGGCCCCCACTGCGTCAAGACCTGCCCGGCAGGAGTCATGGGAGAAAACAACACCCTGGTCTGGAAGTACGCAGACGCCGGCCATGTGTGCCACCTGTGCCATCCAAACTGCACCTACGGATGCACTGGGCCAGGTCTTGAAGGCTGTCCAACGAATGGGCCTAAGATCCCGTCCATCGCCACTGGGATGGTGGGGGCCCTCCTCTTGCTGCTGGTGGTGGCCCTGGGGATCGGCCTCTTCATGCGAAGGCGCCACATCGTTCGGAAGCGCACGCTGCGGAGGCTGCTGCAGGAGAGGGAGCTTGTGGAGCCTCTTACACCCAGTGGAGAAGCTCCCAACCAAGCTCTCTTGAGGATCTTGAAGGAAACTGAATTCAAAAAGATCAAAGTGCTGGGCTCCGGTGCGTTCGGCACGGTGTATAAGGGACTCTGGATCCCAGAAGGTGAGAAAGTTAAAATTCCCGTCGCTATCAAGGAATTAAGAGAAGCAACATCTCCGAAAGCCAACAAGGAAATCCTCGATGAAGCCTACGTGATGGCCAGCGTGGACAACCCCCACGTGTGCCGCCTGCTGGGCATCTGCCTCACCTCCACCGTGCAGCTCATCACGCAGCTCATGCCCTTCGGCTGCCTCCTGGACTATGTCCGGGAACACAAAGACAATATTGGCTCCCAGTACCTGCTCAACTGGTGTGTGCAGATCGCAAAGGGCATGAACTACTTGGAGGACCGTCGCTTGGTGCACCGCGACCTGGCAGCCAGGAACGTACTGGTGAAAACACCGCAGCATGTCAAGATCACAGATTTTGGGCTGGCCAAACTGCTGGGTGCGGAAGAGAAAGAATACCATGCAGAAGGAGGCAAAGTGCCTATCAAGTGGATGGCATTGGAATCAATTTTACACAGAATCTATACCCACCAGAGTGATGTCTGGAGCTACGGGGTGACCGTTTGGGAGTTGATGACCTTTGGATCCAAGCCATATGACGGAATCCCTGCCAGCGAGATCTCCTCCATCCTGGAGAAAGGAGAACGCCTCCCTCAGCCACCCATATGTACCATCGATGTCTACATGATCATGGTCAAGTGCTGGATGATAGACGCAGATAGTCGCCCAAAGTTCCGTGAGTTGATCATCGAATTCTCCAAAATGGCCCGAGACCCCCAGCGCTACCTTGTCATTCAGGGGGATGAAAGAATGCATTTGCCAAGTCCTACAGACTCCAACTTCTACCGTGCCCTGATGGATGAAGAAGACATGGACGACGTGGTGGATGCCGACGAGTACCTCATCCCACAGCAGGGCTTCTTCAGCAGCCCCTCCACGTCACGGACTCCCCTCCTGAGCTCTCTGAGTGCAACCAGCAACAATTCCACCGTGGCTTGCATTGATAGAAATGGGCTGCAAAGCTGTCCCATCAAGGAAGACAGCTTCTTGCAGCGATACAGCTCAGACCCCACAGGCGCCTTGACTGAGGACAGCATAGACGACACCTTCCTCCCAGTGCCTGGTGAGTGGCTTGTCTGGAAACAGTCCTGCTCCTCAACCTCCTCGACCCACTCAGCAGCAGCCAGTCTCCAGTGTCCAAGCCAGGTGCTCCCTCCAGCATCTCCAGAGGGGGAAACAGTGGCAGATTTGCAGACACAGTGAAGGGCGTAAGGAGCAGATAAACACATGACCGAGCCTGCACAAGCTCTTTGTTGTGTCTGGTTGTTTGCTGTACCTCTGTTGTAAGAATGAATCTGCAAAATTTCTAGCTTATGAAGCAAATCACGGACATACACATCTGTATGTGTGAGTGTTCATGATGTGTGTACATCTGTGTATGTGTGTGTGTGTATGTGTGTGTTTGTGACAGATTTGATCCCTGTTCTCTCTGCTGGCTCTATCTTGACCTGTGAAACGTATATTTAACTAATTAAATATTAGTTAATATTAATAAATTTTAAGCTTTATCCAGAAAAAAAAAAAAAAAA
によりコードされ得る(GenBank受け入れ番号BC094761.1)(配列番号:1)。
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLIALNTVERIPLENLQIIRGNMYYENSYALAVLSNYDANKTGLKELPMRNLQGQKCDPSCPNGSCWGAGEENCQKLTKIICAQQCSGRCRGKSPSDCCHNQCAAGCTGPRESDCLVCRKFRDEATCKDTCPPLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPGEWLVWKQSCSSTSSTHSAAASLQCPSQVLPPASPEGETVADLQTQ
によりコードされ得る(GenBank受け入れ番号AAH94761.1)(配列番号:2)。
さらに本明細書においてEGFRの突然変異体と呼ばれる多くの多様な変異体が同定され、また多くのこれらのEGFR変異体は、特定のがんの開始または進行に関与してきた。EGFRの突然変異は、一般にNまたはC末端における小さな欠失である。mRNA中のエクソン2〜7に対応するインフレーム欠失であるEGFRvIIIは、現在、最も一般的なEGFR変異体として公知であり、また多形性膠芽腫(GBM)において最初に同定された。
GTCCGGGCAGCCCCCGGCGCAGCGCGGCCGCAGCAGCCTCCTCCCCCCGCACGGTGTGAGCGCCCGCCGCGGCCGAGGCGGCCGGAGTCCCGAGCTAGCCCCGGCGGCCGCCGCCGCCCAGACCGGACGACAGGCCACCTCGTCGGCGTCCGCCCGAGTCCCCGCCTCGCCGCCAACGCCACAACCACCGCGCACGGCCCCCTGACTCCGTCCAGTATTGATCGGGAGAGCCGGAGCGAGCTCTTCGGGGAGCAGCGATGCGACCCTCCGGGACGGCCGGGGCAGCGCTCCTGGCGCTGCTGGCTGCGCTCTGCCCGGCGAGTCGGGCTCTGGAGGAAAAGAAAGTTTGCCAAGGCACGAGTAACAAGCTCACGCAGTTGGGCACTTTTGAAGATCATTTTCTCAGCCTCCAGAGGATGTTCAATAACTGTGAGGTGGTCCTTGGGAATTTGGAAATTACCTATGTGCAGAGGAATTATGATCTTTCCTTCTTAAAGACCATCCAGGAGGTGGCTGGTTATGTCCTCATGCTCTACAACCCCACCACGTACCAGATGGATGTGAACCCCGAGGGCAAATACACCTTTGGTGCCACCTGCGTGAAGAAGTGTCCCCGTAATTATGTGGTGACAGATCACGGCTCGTGCGTCCGAGCCTGTGGGGCCGACAGCTATGAGATGGAGGAAGACGGCGTCCGCAAGTGTAAGAAGTGCGAAGGGCCTTGCCGCAAAGTGTGTAACGGAATAGGTATTGGTGAATTTAAAGACTCACTCTCCATAAATGCTACGAATATTAAACACTTCAAAAACTGCACCTCCATCAGTGGCGATCTCCACATCCTGCCGGTGGCATTTAGGGGTGACTCCTTCACACATACTCCTCCTCTGGATCCACAGGAACTGGATATTCTGAAAACCGTAAAGGAAATCACAGGGTTTTTGCTGATTCAGGCTTGGCCTGAAAACAGGACGGACCTCCATGCCTTTGAGAACCTAGAAATCATACGCGGCAGGACCAAGCAACATGGTCAGTTTTCTCTTGCAGTCGTCAGCCTGAACATAACATCCTTGGGATTACGCTCCCTCAAGGAGATAAGTGATGGAGATGTGATAATTTCAGGAAACAAAAATTTGTGCTATGCAAATACAATAAACTGGAAAAAACTGTTTGGGACCTCCGGTCAGAAAACCAAAATTATAAGCAACAGAGGTGAAAACAGCTGCAAGGCCACAGGCCAGGTCTGCCATGCCTTGTGCTCCCCCGAGGGCTGCTGGGGCCCGGAGCCCAGGGACTGCGTCTCTTGCCGGAATGTCAGCCGAGGCAGGGAATGCGTGGACAAGTGCAACCTTCTGGAGGGTGAGCCAAGGGAGTTTGTGGAGAACTCTGAGTGCATACAGTGCCACCCAGAGTGCCTGCCTCAGGCCATGAACATCACCTGCACAGGACGGGGACCAGACAACTGTATCCAGTGTGCCCACTACATTGACGGCCCCCACTGCGTCAAGACCTGCCCGGCAGGAGTCATGGGAGAAAACAACACCCTGGTCTGGAAGTACGCAGACGCCGGCCATGTGTGCCACCTGTGCCATCCAAACTGCACCTACGGATGCACTGGGCCAGGTCTTGAAGGCTGTCCAACGAATGGGCCTAAGATCCCGTCCATCGCCACTGGGATGGTGGGGGCCCTCCTCTTGCTGCTGGTGGTGGCCCTGGGGATCGGCCTCTTCATGCGAAGGCGCCACATCGTTCGGAAGCGCACGCTGCGGAGGCTGCTGCAGGAGAGGGAGCTTGTGGAGCCTCTTACACCCAGTGGAGAAGCTCCCAACCAAGCTCTCTTGAGGATCTTGAAGGAAACTGAATTCAAAAAGATCAAAGTGCTGGGCTCCGGTGCGTTCGGCACGGTGTATAAGGGACTCTGGATCCCAGAAGGTGAGAAAGTTAAAATTCCCGTCGCTATCAAGGAATTAAGAGAAGCAACATCTCCGAAAGCCAACAAGGAAATCCTCGATGAAGCCTACGTGATGGCCAGCGTGGACAACCCCCACGTGTGCCGCCTGCTGGGCATCTGCCTCACCTCCACCGTGCAGCTCATCACGCAGCTCATGCCCTTCGGCTGCCTCCTGGACTATGTCCGGGAACACAAAGACAATATTGGCTCCCAGTACCTGCTCAACTGGTGTGTGCAGATCGCAAAGGGCATGAACTACTTGGAGGACCGTCGCTTGGTGCACCGCGACCTGGCAGCCAGGAACGTACTGGTGAAAACACCGCAGCATGTCAAGATCACAGATTTTGGGCTGGCCAAACTGCTGGGTGCGGAAGAGAAAGAATACCATGCAGAAGGAGGCAAAGTGCCTATCAAGTGGATGGCATTGGAATCAATTTTACACAGAATCTATACCCACCAGAGTGATGTCTGGAGCTACGGGGTGACCGTTTGGGAGTTGATGACCTTTGGATCCAAGCCATATGACGGAATCCCTGCCAGCGAGATCTCCTCCATCCTGGAGAAAGGAGAACGCCTCCCTCAGCCACCCATATGTACCATCGATGTCTACATGATCATGGTCAAGTGCTGGATGATAGACGCAGATAGTCGCCCAAAGTTCCGTGAGTTGATCATCGAATTCTCCAAAATGGCCCGAGACCCCCAGCGCTACCTTGTCATTCAGGGGGATGAAAGAATGCATTTGCCAAGTCCTACAGACTCCAACTTCTACCGTGCCCTGATGGATGAAGAAGACATGGACGACGTGGTGGATGCCGACGAGTACCTCATCCCACAGCAGGGCTTCTTCAGCAGCCCCTCCACGTCACGGACTCCCCTCCTGAGCTCTCTGAGTGCAACCAGCAACAATTCCACCGTGGCTTGCATTGATAGAAATGGGCTGCAAAGCTGTCCCATCAAGGAAGACAGCTTCTTGCAGCGATACAGCTCAGACCCCACAGGCGCCTTGACTGAGGACAGCATAGACGACACCTTCCTCCCAGTGCCTGGTGAGTGGCTTGTCTGGAAACAGTCCTGCTCCTCAACCTCCTCGACCCACTCAGCAGCAGCCAGTCTCCAGTGTCCAAGCCAGGTGCTCCCTCCAGCATCTCCAGAGGGGGAAACAGTGGCAGATTTGCAGACACAGTGAAGGGCGTAAGGAGCAGATAAACACATGACCGAGCCTGCACAAGCTCTTTGTTGTGTCTGGTTGTTTGCTGTACCTCTGTTGTAAGAATGAATCTGCAAAATTTCTAGCTTATGAAGCAAATCACGGACATACACATCTGTATGTGTGAGTGTTCATGATGTGTGTACATCTGTGTATGTGTGTGTGTGTATGTGTGTGTTTGTGACAGATTTGATCCCTGTTCTCTCTGCTGGCTCTATCTTGACCTGTGAAACGTATATTTAACTAATTAAATATTAGTTAATATTAATAAATTTTAAGCTTTATCCAGAAAAAAAAAAAAAAAA(配列番号:3)。
GCTGGCTGCGCTCTGCCCGGCGAGTCGGGCTCTGGAGGAAAAGAAAGTTTGCCAAGGCACGAGTAACAAGCTCACGCAGTTGGGCACTTTTGAAGATCATTTTCTCAGCCTCCAGAGGATGTTCAATAACTGTGAGGTGGTCCTTGGGAATTTGGAAATTACCTATGTGCAGAGGAATTATGATCTTTCCTTCTTAAAGACCATCCAGGAGGTGGCTGGTTATGTCCTCATGCTCTACAACCCCACCACGTACCAGATGGATGTGAACCCCGAGGGCAAATACACCTTTGGTGCCACCTGCGTGAAGAAGTGTCCCCGTAATTATGTGGTGACAGATCACGGCTCGTGCGTCCGAGCCTGTGGGGCCGACAGCTATGAGATGGAGGAA(配列番号:4)。
MRPSGTAGAALLALLAALCPASRALEEKKVCQGTSNKLTQLGTFEDHFLSLQRMFNNCEVVLGNLEITYVQRNYDLSFLKTIQEVAGYVLMLYNPTTYQMDVNPEGKYSFGATCVKKCPRNYVVTDHGSCVRACGADSYEMEEDGVRKCKKCEGPCRKVCNGIGIGEFKDSLSINATNIKHFKNCTSISGDLHILPVAFRGDSFTHTPPLDPQELDILKTVKEITGFLLIQAWPENRTDLHAFENLEIIRGRTKQHGQFSLAVVSLNITSLGLRSLKEISDGDVIISGNKNLCYANTINWKKLFGTSGQKTKIISNRGENSCKATGQVCHALCSPEGCWGPEPRDCVSCRNVSRGRECVDKCNLLEGEPREFVENSECIQCHPECLPQAMNITCTGRGPDNCIQCAHYIDGPHCVKTCPAGVMGENNTLVWKYADAGHVCHLCHPNCTYGCTGPGLEGCPTNGPKIPSIATGMVGALLLLLVVALGIGLFMRRRHIVRKRTLRRLLQERELVEPLTPSGEAPNQALLRILKETEFKKIKVLGSGAFGTVYKGLWIPEGEKVKIPVAIKELREATSPKANKEILDEAYVMASVDNPHVCRLLGICLTSTVQLITQLMPFGCLLDYVREHKDNIGSQYLLNWCVQIAKGMNYLEDRRLVHRDLAARNVLVKTPQHVKITDFGLAKLLGAEEKEYHAEGGKVPIKWMALESILHRIYTHQSDVWSYGVTVWELMTFGSKPYDGIPASEISSILEKGERLPQPPICTIDVYMIMVKCWMIDADSRPKFRELIIEFSKMARDPQRYLVIQGDERMHLPSPTDSNFYRALMDEEDMDDVVDADEYLIPQQGFFSSPSTSRTPLLSSLSATSNNSTVACIDRNGLQSCPIKEDSFLQRYSSDPTGALTEDSIDDTFLPVPGEWLVWKQSCSSTSSTHSAAASLQCPSQVLPPASPEGETVADLQTQ(配列番号:5)。
フラグメント、誘導体及びその類似物を含める本発明のEGFR変異体は、後に発表する診断、研究、及び治療方法における用途を有する抗体を産するための免疫原として使用され得る。抗体は、ポリクローナルまたはモノクローナル、キメラ、ヒト化、単鎖(svFc)またはFabフラグメントであり得る。通常の当業者に公知である多様な手順は、かかる抗体及びフラグメントの生産及び標識化のために使用され得る。例えばBurns、編、Immunochemical Protocols、第3補改訂編、Humana Press(2005);Harlow and Lane、Antibodies:A Laboratory Manual、Cold Spring Harbor Laboratory(1988);Kozbor等、Immunology Today 4:72(1983);Kohler及びMilstein、Nature 256:495(1975)を参照する。
本発明は、EGFRvVIを直接的または間接的に検出するような診断方法に基づくDNA、RNA及びタンパク質を提供する。さらに本発明は、診断目的のための組成物及びキットを提供する。
本明細書において使用される用語“生体試料”とは、DNA、RNA及びタンパク質等の生体材料を含む試料に言及する。いくつかの態様では、生体試料は、組織試料、細胞培養試料、または生検試料であり得る。いくつかの態様では、生体試料は、対象から由来する体液を適切に含んで成り得る。体液は、これらに限定されないが、例えば血液、血漿、血清、尿、唾液、髄液、脳脊髄液、胸膜液、乳頭吸引液、リンパ液、気道液、腸液、尿生殖路の液体、涙液、唾液、母乳、リンパ系から由来する液体、精液、脳脊髄液、臓器内系統の液体、腹水、腫瘍嚢胞液、羊水及びその組み合わせを含める対象の体のいずれの場所からでも単離される、好適には末梢の位置から単離される液体であり得る。いくつかの態様では、生体試料として使用するために好適な体液は、尿である。他の態様では、好適な体液は、脳脊髄液(CSF)、血清または血漿である。適切には、約0.1mL〜約30mLの液体の試料容積が使用され得る。液体の容積は、いくつかの要因、例えば使用される液体のタイプに左右され得る。例えば血清試料の容積は、約0.1mL〜約20mL、好適には約4mLであり得る。尿試料の容積は、約10mL〜約30mL、好適には約20mLであり得る。
EGFRvVIは、これらに限定されないが、核酸シークエンシング;核酸ハイブリダイゼーション;及び核酸増幅を含める通常の当業者に公知である多様な核酸技術を使用して、ゲノムDNAまたはキメラmRNAの染色体再配置として検出され得る。
EGFR Forw 1− CTGCTGGCTGCGCTCTG(配列番号:6)
EGFRv3 rev4 - CGTGATCTGTCACCACATAATTACC(配列番号:7)
EGFR プローブ6 - TTCCTCCAGAGCCCGACT(配列番号:8)
EGFR Forw 1− CTGCTGGCTGCGCTCTG(配列番号:6)
EGFR Rev 1− TTCCTCCATCTCATAGCTGTCG(配列番号:9)
EGFR プローブ6: TTCCTCCAGAGCCCGACT(配列番号:8)
EGFR qPCR エクソン3〜7 del forw 1: TGGTCCTTGGGAATTTGGAA(配列番号:10)
EGFR qPCR エクソン3〜7 del rev: GTGGGGTTGTAGAGCATGAGGA(配列番号:11)
EGFR qPCR エクソン3〜7 del プローブ: TACCTATGTGCAGAGGAA(配列番号:12)を含める。
本発明のEGFRvVIは、これらに限定されないが、タンパク質シークエンシング及び免疫測定法を含める通常の当業者に公知である多様なタンパク質技術を用いて、先を切断されたEGFRタンパク質、キメラタンパク質または欠失を伴うタンパク質として検出され得る。タンパク質シークエンシング技術の例は、これらに限定されないが、質量分析法及びエドマン分解を含める。免疫測定法の例は、これらに限定されないが、免疫沈降、ウエスタンブロット法、ELISA、免疫組織化学、免疫細胞化学、フローサイトメトリー、及び免疫−PCRを含める。通常の当業者に公知である多様な技術(例えば熱量測定、蛍光、化学発光または放射性標識)を用いて、検出可能な部分により標識化されたポリクローナルまたはモノクローナル抗体は、免疫測定における使用に適している。
本発明の診断方法において使用するための組成物は、これらに限定されないがプローブ、増幅オリゴヌクレオチド、及び抗体を含める。特に好適な組成物は、任意の他のEGFR変異体ではなく、EGFRvVIを検出する。これらの組成物は、EGFRのエクソンからの5’部分が、エクソン7からの3’部分に結合するジャンクションとハイブリダイズする配列を含んで成る単一の標識化プローブまたはオリゴヌクレオチドプライマー;エクソン3及びエクソン7が、EGFRvVI中でつながるところで、一つの増幅オリゴヌクレオチドが、相同の切断点にハイブリダイズする配列を含んで成る、一対の増幅オリゴヌクレオチド;またはEGFRvVIを特異的に認識する抗体を含める。
EGFRvVI及びがんを伴う患者の予後診断の間で、相関性は存在し得る。いくつかの態様では、EGFRvVIの存在、不存在またはそのレベルは、その活性、悪性度、侵襲性、または転移能に基づき、腫瘍を、階層化または分類するための用途であり得る。したがって、いくつかの態様では、EGFRvVIを検出するためのアッセイは、予後診断を提供し、そして医師が適切な治療戦略を決定するのを助けるために使用される。例えば、いくつかの態様では、EGFRvVIを有する腫瘍を伴う患者は、野生型EGFRを有するものとは別に治療される。例えば、EGFRvVIを有する患者の予後診断は、EGFRvVIを欠く患者よりも悪くなり得るので、より積極的な治療計画を要求し得る。いくつかの態様では、EGFRvVIの存在は、生存率/時間、腫瘍の侵襲性、及び転移と相関する。
いくつかの態様では、本発明は、薬物スクリーニングアッセイ(例えば抗がん剤をスクリーニングする)を提供する。本発明のスクリーニング方法は、EGFRvVIの生物学的機能を調節し得る化合物または化学物質(例えば小分子、薬物、タンパク質、ペプチド、ペプチド模倣物、ペプトイド)の同定を提供する。例えば化合物または化学物質は、EGFRvVIがリガンド結合ドメインの一部を欠いているような、リガンド非依存性の方法において、EGFRvVIを阻害し得る。EGFRvVIの生物学的機能の阻害は、EGFRキナーゼ活性を阻害すること、EGFRvVIの上流もしくは下流であるシグナル経路を調節すること、またはEGFRvVIのプロテアソーム分解を増加させることを含め得る。EGFRvVIの活性を阻害する化合物は、増殖性疾患、例えばがんの治療において有用であり得る。
本実施例では、患者(患者ID UCS−0001)からグリオーマ脳脊髄液(CSF)試料を得た。生検では、EGFRvIII陽性であった。微小胞は、4mLのCSF試料から抽出した。核酸、例えばRNAは、当業界において公知の方法により抽出した。
EGFR Forw 1− CTGCTGGCTGCGCTCTG(配列番号:6)
EGFRv3 rev4 - CGTGATCTGTCACCACATAATTACC(配列番号:7)
EGFRプローブ6 - TTCCTCCAGAGCCCGACT(FAM−染料で標識されたMinor Grove Binder (MGB)プローブ)(配列番号:8)を使用した。
EGFR Forw 1− CTGCTGGCTGCGCTCTG(配列番号:6)
EGFR Rev 1− TTCCTCCATCTCATAGCTGTCG(配列番号:9)
EGFRプローブ6− TTCCTCCAGAGCCCGACT (FAM−染料で標識されたMinor Grove Binder (MGB)プローブ)(配列番号:8)を使用した。
EGFR Forw 1 (18μM) 1μL
EGFR Rev 1 (18μM) 1μL
dNTPs (10mM) 1μL
HF酵素緩衝剤 (5×) 10μL
Phusion ホットスタート II DNA ポリメラーゼ 0.5μL
DMSO 1.5μL
H2O 30μL
cDNA 5μL
を使用した。
1.98℃、30秒
2.98℃、10秒
3.62℃、15秒
4.72℃、15秒
5.72℃、5分
ステップ2〜4を、36サイクルで繰り返す。
EGFR qPCR エクソン3〜7 del forw 1: TGGTCCTTGGGAATTTGGAA(配列番号:10)
EGFR qPCR エクソン3〜7 del rev: GTGGGGTTGTAGAGCATGAGGA(配列番号:11)
EGFR qPCR エクソン3〜7 del プローブ(FAMMGB): TACCTATGTGCAGAGGAA(配列番号:12)である。
Claims (20)
- 野生型EGFRのエクソン3において始まり、そしてエクソン7において終わるインフレーム欠失を含んで成る、単離上皮成長因子受容体(EGFR)タンパク質。
- アミノ酸90〜221が欠失している、請求項1に記載された単離上皮成長因子受容体(EGFR)タンパク質。
- 前記EGFRタンパク質が、配列番号:5のアミノ酸配列を含んで成る、請求項1に記載された単離上皮成長因子受容体(EGFR)タンパク質。
- アミノ酸90〜221をコードするヌクレオチドが欠失している、上皮成長因子受容体(EGFR)をコードする単離ポリヌクレオチド。
- ポリヌクレオチドが、配列番号3または4のヌクレオチド配列を含んで成る、上皮成長因子受容体(EGFR)をコードする単離ポリヌクレオチド。
- 請求項1〜3のいずれか1項に記載されたEGFRタンパク質と結合する抗体。
- 請求項1〜5のいずれか1項に記載されたEGFRタンパク質またはポリヌクレオチドの存在について生体試料を分析することを含んで成り、当該EGFRタンパク質またはポリヌクレオチドの存在が、がんの存在、またはがんの発達への対象のより高い素因を示す、対象におけるがんを診断するための方法。
- 前記がんが、神経系のがん、または上皮がんである、請求項7に記載された方法。
- 前記神経系のがんが、膠芽腫または多形性膠芽腫である、請求項8に記載された方法。
- 前記上皮がんが、結腸がん、肺がん、前立腺がん、乳がんまたは他の固形腫瘍がんである、請求項8に記載された方法。
- 治療計画への対象の応答性を評価するための方法であって、対象に由来する生体試料を提供する工程、及び請求項1〜5のいずれか1項に記載されたEGFRタンパク質またはポリヌクレオチドの存在、不存在、または発現のレベルを決定する工程、を含んで成り、当該EGFRタンパク質またはポリヌクレオチドの存在、不存在、または発現のレベルが、当該治療計画への対象の応答性を示す、当該方法。
- 前記治療計画が、EGFR阻害剤を含んで成る、請求項11に記載された方法。
- 治療計画を推奨するための方法であって、対象に由来する生体試料を提供する工程、請求項1〜5のいずれか1項に記載されたEGFRタンパク質またはポリヌクレオチドの存在を決定する工程、を含んで成り、当該EGFRタンパク質またはポリヌクレオチドの存在が、EGFR阻害剤を含んで成る治療計画を除外する、当該方法。
- 前記EGFR阻害剤が、EGFR発現または活性化を阻害する小分子、RNAi剤、抗体、または薬物である、請求項12または13に記載された方法。
- EGFRタンパク質に特異的に結合する化学物質を対象に投与することを含んで成る、請求項1〜3のいずれか1項に記載されたEGFRタンパク質を発現するがん細胞を標的にするための方法。
- 前記化学物質が抗体である、請求項15に記載された方法。
- 前記抗体が、治療剤に共有結合している、請求項15または16に記載された方法。
- 前記治療剤が、化学療法剤、抗がん剤、毒素、ラジオアイソトープ、またはナノ粒子である、請求項17に記載された方法。
- 請求項1〜3のいずれか1項に記載されたEGFRの阻害剤を対象に投与することを含んで成る、がん、またはその兆候を治療するための方法。
- 前記阻害剤が、請求項1〜3のいずれか1項に記載されたEGFRの発現または活性化を阻害する小分子、RNAi剤、抗体、または薬物である、請求項19に記載された方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201361765537P | 2013-02-15 | 2013-02-15 | |
US61/765,537 | 2013-02-15 | ||
PCT/US2014/016536 WO2014127266A1 (en) | 2013-02-15 | 2014-02-14 | A novel egfr variant |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2016508519A true JP2016508519A (ja) | 2016-03-22 |
JP6673698B2 JP6673698B2 (ja) | 2020-03-25 |
Family
ID=51354583
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015558160A Active JP6673698B2 (ja) | 2013-02-15 | 2014-02-14 | 新規のegfr変異体 |
Country Status (6)
Country | Link |
---|---|
US (2) | US20160075788A1 (ja) |
EP (1) | EP2956554B1 (ja) |
JP (1) | JP6673698B2 (ja) |
AU (1) | AU2014216135B2 (ja) |
CA (1) | CA2901518C (ja) |
WO (1) | WO2014127266A1 (ja) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ES2744589T3 (es) * | 2011-05-11 | 2020-02-25 | Exosome Diagnostics Inc | Extracción de ácido nucleico de materiales biológicos heterogéneos |
WO2016210147A1 (en) * | 2015-06-23 | 2016-12-29 | Abbott Molecular Inc. | Egfr assay |
CN111133106A (zh) | 2017-07-12 | 2020-05-08 | 外来体诊断公司 | 用于分离和富集生物流体来源的细胞外囊泡的方法及其使用方法 |
CN113354715B (zh) * | 2021-05-07 | 2023-03-17 | 暨南大学 | Egfr的改造的结合蛋白及其应用 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007526233A (ja) * | 2003-06-27 | 2007-09-13 | アブジェニックス・インコーポレーテッド | 上皮成長因子受容体の欠失型変異体を認識する抗体、およびそれらの使用 |
WO2008119562A1 (en) * | 2007-04-03 | 2008-10-09 | Bergen Teknologioverforing As | Method and kits for detection of egfrviii |
JP2009532358A (ja) * | 2006-03-31 | 2009-09-10 | マサチューセッツ・インスティテュート・オブ・テクノロジー | 突然変異型egf受容体を発現する腫瘍の治療 |
JP2010530754A (ja) * | 2007-06-22 | 2010-09-16 | イントラダイム コーポレイション | ヒトEGFR−siRNAを含む組成物および使用方法 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4965188A (en) | 1986-08-22 | 1990-10-23 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences using a thermostable enzyme |
US4683195A (en) | 1986-01-30 | 1987-07-28 | Cetus Corporation | Process for amplifying, detecting, and/or-cloning nucleic acid sequences |
US4683202A (en) | 1985-03-28 | 1987-07-28 | Cetus Corporation | Process for amplifying nucleic acid sequences |
US4800159A (en) | 1986-02-07 | 1989-01-24 | Cetus Corporation | Process for amplifying, detecting, and/or cloning nucleic acid sequences |
US5710029A (en) | 1995-06-07 | 1998-01-20 | Gen-Probe Incorporated | Methods for determining pre-amplification levels of a nucleic acid target sequence from post-amplification levels of product |
US6303305B1 (en) | 1999-03-30 | 2001-10-16 | Roche Diagnostics, Gmbh | Method for quantification of an analyte |
DE60014762T2 (de) | 1999-05-24 | 2005-10-13 | Tosoh Corp., Shinnanyo | Methode zum Nachweis von Ribonukleinsäuren |
CA2466896A1 (en) | 2001-09-06 | 2003-03-20 | Adnagen Ag | Method and diagnosis kit for selecting and or qualitative and/or quantitative detection of cells |
WO2006048291A2 (en) * | 2004-11-03 | 2006-05-11 | Almac Diagnostics Limited | Transcriptome microarray technology and methods of using the same |
EP2118320A4 (en) * | 2007-02-06 | 2010-05-19 | Genizon Biosciences Inc | GENE CARD OF HUMAN GENES ASSOCIATED WITH HYPERACTIVITY ATTENTION DEFICIT DISORDER (ADHD) |
-
2014
- 2014-02-14 EP EP14751442.6A patent/EP2956554B1/en active Active
- 2014-02-14 WO PCT/US2014/016536 patent/WO2014127266A1/en active Application Filing
- 2014-02-14 US US14/768,275 patent/US20160075788A1/en not_active Abandoned
- 2014-02-14 AU AU2014216135A patent/AU2014216135B2/en active Active
- 2014-02-14 JP JP2015558160A patent/JP6673698B2/ja active Active
- 2014-02-14 CA CA2901518A patent/CA2901518C/en active Active
-
2019
- 2019-01-29 US US16/261,241 patent/US20190211106A1/en not_active Abandoned
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2007526233A (ja) * | 2003-06-27 | 2007-09-13 | アブジェニックス・インコーポレーテッド | 上皮成長因子受容体の欠失型変異体を認識する抗体、およびそれらの使用 |
JP2009532358A (ja) * | 2006-03-31 | 2009-09-10 | マサチューセッツ・インスティテュート・オブ・テクノロジー | 突然変異型egf受容体を発現する腫瘍の治療 |
WO2008119562A1 (en) * | 2007-04-03 | 2008-10-09 | Bergen Teknologioverforing As | Method and kits for detection of egfrviii |
JP2010530754A (ja) * | 2007-06-22 | 2010-09-16 | イントラダイム コーポレイション | ヒトEGFR−siRNAを含む組成物および使用方法 |
Non-Patent Citations (5)
Title |
---|
CANCER RESEARCH, vol. 55, no. 23, JPN6017046588, 1995, pages 5536 - 5539, ISSN: 0004182919 * |
CANCER RESEARCH, vol. 72, no. 12, JPN6018043494, 2012, pages 1 - 7, ISSN: 0004182922 * |
CELL GROWTH AND DIFFERENTIATION, vol. 6, JPN6017046590, 1995, pages 1251 - 1259, ISSN: 0004182920 * |
JAPANESE JOURNAL OF CANCER RESSEARCH, vol. 81, no. 8, JPN6017046586, 1990, pages 773 - 779, ISSN: 0004182918 * |
NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY, vol. 35, no. 2, JPN6017046584, 2009, pages 208 - 213, ISSN: 0004182921 * |
Also Published As
Publication number | Publication date |
---|---|
EP2956554A1 (en) | 2015-12-23 |
US20190211106A1 (en) | 2019-07-11 |
CA2901518A1 (en) | 2014-08-21 |
AU2014216135A1 (en) | 2015-09-03 |
CA2901518C (en) | 2022-09-13 |
WO2014127266A1 (en) | 2014-08-21 |
EP2956554B1 (en) | 2019-10-09 |
AU2014216135B2 (en) | 2019-10-24 |
EP2956554A4 (en) | 2016-10-05 |
US20160075788A1 (en) | 2016-03-17 |
JP6673698B2 (ja) | 2020-03-25 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2882759C (en) | Detection of the ntrk1-mprip gene fusion for cancer diagnosis | |
US20190211106A1 (en) | Novel egfr variant | |
CA2767914C (en) | Markers for endometrial cancer | |
CA2676179C (en) | Metastasis specific splice variants of mena and uses thereof in diagnosis, prognosis and treatment of tumors | |
US20190048424A1 (en) | Biomarkers of Response to Inhibition of Poly-ADP Ribose Polymerase (PARP) in Cancer | |
CN102533958A (zh) | 一种检测人pik3ca基因突变的方法和试剂盒 | |
EP2304051B1 (en) | Human mena isoform serve as marker for sensitivity to egfr inhibition in human cancer cells | |
US20150344964A1 (en) | Prediction of the treatment response to an anti-egfr molecule in colorectal cancer patients | |
WO2012131092A2 (en) | Method and kits for the prediction of response/nonresponse to the treatment with an anti-egfr antibody in patients with colorectal cancer of all uicc stages | |
US11015224B2 (en) | RAF gene fusions | |
KR20150085459A (ko) | 대장암 마커로서의 신규 ntrk1 융합유전자 및 이의 용도 | |
JP2012085556A (ja) | 乳がんの診断方法 | |
JP2012085555A (ja) | 乳がん診断用マーカー | |
JP5467256B2 (ja) | 消化器癌検出用血清腫瘍マーカー、消化器癌検出キット、および消化器癌検出方法 | |
EP2508619A1 (en) | Method and kits for the prediction of response/nonresponse to the treatment with an anti-EGFR antibody in patients with colorectal cancer of all UICC stages | |
EP2702409A1 (en) | Cxcr1 as a predictor of response to treatment with epidermal growth factor receptor therapeutic | |
Ghazizadeh et al. | GENOMIC ANALYSIS OF ONE ALLELE OF A GENE HER2/NEU, ERBB1, BRCA1, BRCA2 IN THE INCIDENCE OF BREAST CANCER IN WOMEN WITH A FAMILY HISTORY HETROZYGOUSTY WITH MENSTRUAL CYCLE DISORDERS | |
KR20180132376A (ko) | 대장암 진단 마커로서의 신규 folr2 융합유전자 및 이의 용도 | |
US20100216148A1 (en) | Novel tumor marker | |
KR20150012090A (ko) | 항-안지오포이에틴 2 항체에 대한 임상 마커 및 이의 이용 | |
JP2014519330A (ja) | Her2阻害薬を用いた治療に対する応答を予測する方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20170124 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20171122 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20171205 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20180302 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180604 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20181106 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190205 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20190611 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190911 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20191122 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20200107 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200122 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20200204 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20200305 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6673698 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |