Classifications

• • 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
  • G01N33/57407—Specifically defined cancers
  • G01N33/57438—Specifically defined cancers of liver, pancreas or kidney
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
  • A61K31/45—Non condensed piperidines, e.g. piperocaine having oxo groups directly attached to the heterocyclic ring, e.g. cycloheximide
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
• • 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
  • 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
• • 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
  • C12Q2600/136—Screening for pharmacological compounds

Definitions

• biomarkers for use in predicting the clinical sensitivity of a solid tumor, and a subject's response to treatment with an immunomodulatory agent such as 3-(5- amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione ("Compound A").
• a solid tumor is an abnormal mass of tissue that usually does not contain cysts or liquid areas.
• Solid tumors may be benign or malignant.
• a solid tumor grows in an anatomical site outside the bloodstream (in contrast, for example, to cancers of hematopoietic origin such as leukemias) and requires the formation of small blood vessels and capillaries to supply nutrients, etc. to the growing tumor mass.
• Solid tumors are named for the type of cells that form them.
• Non-limiting examples of solid tumors are sarcomas, carcinomas (epithelial tumors),
• exemplary solid tumors include biliary cancer (e.g., biliary cancer
• cholangiocarcinoma bladder cancer
• breast cancer e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast
• brain cancer e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma, glioblastomas; medulloblastoma
• cervical cancer e.g., cervical adenocarcinoma
• colorectal cancer e.g., colon cancer, rectal cancer, colorectal adenocarcinoma
• gastric cancer e.g., stomach adenocarcinoma
• GIST gastrointestinal stromal tumor
• head and neck cancer e.g. , head and neck squamous cell carcinoma
• oral cancer e.g., oral squamous cell carcinoma (OSCC)
• kidney cancer e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell carcinoma
• liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
• lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
• SCLC small cell lung cancer
• NSCLC non-small cell lung cancer
• adenocarcinoma of the lung e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
• neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis
• neuroendocrine cancer e.g., gastroenteropancreatic neuroendocrine tumor (GEP-NET), carcinoid tumor), osteosarcoma
• ovarian cancer e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma
• pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)
• prostate cancer e.g., prostate cancer
• adenocarcinoma skin cancer
• skin cancer e.g., squamous cell carcinoma (SCC), keratoacanthoma ( A), melanoma, basal cell carcinoma (BCC)
• soft tissue sarcoma e.g. , malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma, osteosarcoma).
• HCC Hepatocellular carcinoma
• HCC also known as malignant hepatoma
• HCC is the most common primary malignancy of the liver and accounts for 80-90% of primary liver tumors.
• HCC is one of the most common and devastating malignant diseases worldwide, responsible for more than 1 million deaths annually in the world (Parkin et al, CA Cancer J. Clin. 1999, 49, 33-64; Bruix et al., Cancer Cell 2004, 5, 215-219).
• HCC hepatitis B or C viral infection
• alcoholic liver disease Rustgi, Gastroenterol. Clin. North Am. 1987, 16, 545-551; Bosch et al, Semin. Liver Dis. 1999, 19, 271-285; Bosch et al, Gastroenterology 2004, 127, S5- S16; Moradpour et al, Eur. J. Gastro & Hepatol. 2005, 17, 477-483; Koike et al., J.
• HCC hepatitis B virus
• HCV hepatitis C virus
• HCC Gastroenterol. Hepatol. 2005, 3, 132-135.
• HCC is associated with HBV infection in about 50%> of cases (Liaw, Semin. Liver Dis. 2005, 25, 40-47).
• HCV infection is the cause of 70%> of the cases of HCC in Japan (Hasan, et al, Hepatology, 1990, 12:589-591; El-Serag et al, N. Engl. J. Med. 1999, 340, 745-750).
• HCC incidence has been increasing in Western countries in recent years due to the spread of hepatitis C virus (HCV) infection (El-Serag, Hepatology 2002, 36, S74-83; Trevisani et al, Carcinogenesis 2008, 29, 1299-1305).
• HCV hepatitis C virus
• HCC is a disease of worldwide significance, of which there is no truly effective therapy, particularly for advanced disease. Therefore, there is a need for biomarkers to aid a HCC treatment and a method of predicting the responsiveness of a HCC subject to a HCC treatment, e.g., chemotherapy.
• GBM Glioblastoma
• Glioblastomas are tumors that arise from astrocytes or supportive tissue of the brain. Glioblastomas are generally found in the cerebral hemispheres of the brain, but can be found anywhere in the brain or spinal cord. These tumors are usually highly malignant
• Glioblastomas usually contain a mix of cell types. It is common for these tumors to contain cystic mineral, calcium deposits, blood vessels, or a mixed grade of cells. There are two types of glioblastomas. The first type of glioblastoma is primary or de novo. The tumors of the first type are very aggressive, and tend to form and make their presence quickly. The second type of glioblastoma is secondary. These tumors have a longer, somewhat slower growth history, yet aggressive. They may begin as lower-grade tumors which eventually become higher grade.
• glioblastomas The symptoms of glioblastomas are usually caused by increased pressure in the brain, including headache, nausea, vomiting, and drowsiness. Like many tumor types, the exact cause of glioblastoma is not known.
• the glioblastomas usually contain many different types of cells— some cells may respond well to certain therapies, while others may not be affected at all, thus they are usually difficult to treat and the treatment usually involve combinations of various approaches.
• CRBN protein cereblon
• SLOl calcium- activated potassium channel protein
• CIC-2 voltage-gated chloride channel
• DDB1 was originally identified as a nucleotide excision repair protein that associates with damaged DNA binding protein 2 (DDB2). Its defective activity causes the repair defect in the patients with xeroderma pigmentosum complementation group E (XPE).
• DDB1 also appears to function as a component of numerous distinct DCX (DDBl-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
• DCX DDBl-CUL4-X-box
• E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
• CRBN has also been identified as a target for the development of therapeutic agents for diseases of the cerebral cortex. See WO 2010/137547 Al .
• CRBN has recently been identified as a key molecular target that binds to thalidomide to cause birth defects. See Ito, T. et al, Science, 2010, 327: 1345-1350. DDB1 was found to interact with CRBN and, thus, was indirectly associated with thalidomide. Moreover, thalidomide was able to inhibit auto-ubiquitination of CRBN in vitro, suggesting that
• thalidomide is an E3 ubiquitin-ligase inhibitor. Id. Importantly, this activity was inhibited by thalidomide in wild-type cells, but not in cells with mutated CRBN binding sites that prevent thalidomide binding. Id. The thalidomide binding site was mapped to a highly conserved C- terminal 104 amino acid region in CRBN. Id. Individual point mutants in CRBN, Y384A and W386A were both defective for thalidomide binding, with the double point mutant having the lowest thalidomide-binding activity. Id. A link between CRBN and the teratogenic effect of thalidomide was confirmed in animal models of zebra-fish and chick embryos. Id.
• Compounds for the methods provided herein include, but are not limited to, the substituted 2-(2,6-dioxopiperidin-3-yl) phthalimides and substituted 2-(2,6-dioxopiperidin-3-yl)- 1-oxoisoindoles described in U.S. Patent Nos. 6,281,230 and 6,316,471, both to G.W. Muller, et al. Still other specific compounds disclosed herein belong to a class of isoindole-imides disclosed in U.S. Patent Nos. 6,395,754, 6,555,554, 7,091,353, U.S. Publication No.
• Thalidomide, lenalidomide and pomalidomide have shown remarkable responses in patients with multiple myeloma, lymphoma and other hematological diseases such as myelodysplasia syndrome. See Galustian C, et al, Expert Opin Pharmacother., 2009, 10: 125- 133. These treatment compounds display a broad spectrum of activity, including anti-angiogenic properties, modulation of pro-inflammatory cytokines, co-stimulation of T cells, increased NK cell toxicity, direct anti-tumor effects and modulation of stem cell differentiation.
• thalidomide and lenalidomide have emerged as important options for the treatment of multiple myeloma in newly diagnosed patients, in patients with advanced disease who have failed chemotherapy or transplantation, and in patients with relapsed or refractory multiple myeloma.
• Lenalidomide in combination with dexamethasone has been approved for the treatment of patients with multiple myeloma who have received at least one prior therapy.
• Pomalidomide may also be administered in combination with dexamethasone.
• U.S. Patent Publication No. 2004/0029832 Al the disclosure of which is hereby incorporated in its entirety, discloses the treatment of multiple myeloma.
• Compound A 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3- yl)-piperidine-2,6-dione
• Compound A can be prepared as described in U.S. Pat. No. 7,635,700, the disclosure of which is incorporated herein by reference in its entirety.
• the compound can be also synthesized according to other methods apparent to those of skill in the art based upon the teaching herein.
• Compound A is in a crystalline form described in U.S. Provisional Pat. App. No. 61/451,806, filed March 11, 2011, which is incorporated herein by reference in its entirety.
• the hydrochloride salt of Compound A is used in the methods provided herein. Methods of treating, preventing and/or managing cancers and other diseases using Compound A are described in U.S. Provisional Pat. App. No. 61/451,995, filed March 11, 2011, which is incorporated herein by reference in its entirety.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• biomarker determining the level of a biomarker in the sample from the subject, wherein the biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• biomarker is selected from the group consisting of biomarkers identified in Table 1, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• biomarker is selected from the group consisting of biomarkers identified in Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor, e.g., HCC or GBM, in a subject with a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of solid tumor e.g., HCC or GBM, in a subject with a treatment compound, comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ARHGAP19, ASNS, ASPM, ATP2B4,
• PRDM15 PRNP, PTAFR, PTMS, PTTG1, PYROXD1, QPRT, RAB13, RASA4B, RASSF6, RCNl, RGCC, RGSl, RGS2, RNF213, S100A13, SAMD9L, SAMHDl, SEC14L1, SERPINHl, SGOLl, SGOL2, SLC03A1, SLC04A1, SLFNl l, SLFN13, SLFN5, SPl lO, SP140, SPN, SPR, STAP1, STAT1, STAT2, TACC3, TAP1, TAX1BP3, THEMIS2, THTPA, TIMM8B,
• any combination of two or more of the above-identified biomarkers is also contemplated.
• the biomarker is selected from a group consisting of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ATP2B4, BMF, BST2, C10orf76, C19orf66, CD36, CLN3, CNN3, COROIB, CPNE2, CRBN, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHX58, DLG2, DTX3L, EIF2AK2,EPB41L1, ETV6, EXTL2, F13A1, FAM65B, FCGR2B, FES, FMNL3, GBP1, GMFG, GMPR, HIP1, HLA-B, HLA-DMA, HPSE, ID3, IFI35, IFIHl, IFITl, IFIT3, IFIT5, IFITM2, IL4I1, IRF7, IRF9, ISG15, ISG20, ITGB7, JAK3, LAP3, LGALS1, LGALS
• SAMD9L SAMHDl, SERPINHl, SLFNl l, SLFN13, SLFN5, SPl lO, SP140,SPN, SPR, STAP1, STAT1, STAT2, TAP1, TAX1BP3, THEMIS2, THTPA, TNFAIP8L2, TNFSF8, TP53I3, TREXl, TRIM22, TTC39C, TXNIP, UBA7, UBE2L6, USP41, VCL, VNN2 and ZBTB38.
• the biomarker is selected from a group consisting of ARHGAP19, ASNS, ASPM, B4GALT3, BANK1,
• the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN. In another specific embodiment of the various methods provided herein, the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KAT1/CCBL1. In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198.
• the level of only one biomarker is determined. In other embodiments of the various methods provided herein, the levels of two, three, four, five or more biomarkers are determined.
• the reference is prepared by using a control sample obtained from the subject prior to administration of the treatment compound to the subject; and wherein the control sample is from the same source as the sample.
• the reference is prepared by using a control sample obtained from a healthy subject not having the solid tumor; and wherein the control sample is from the same source as the sample.
• the levels of one or more of the biomarkers are measured by determining the mRNA levels of the biomarkers.
• the levels of one or more of the biomarkers are measured by determining the cDNA levels of the biomarkers.
• the levels of one or more of the biomarkers are measured by determining the protein levels of the biomarkers.
• the method provided herein further comprises contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the biomarker protein, and wherein the second antibody immunospecifically binds to a different epitope on the biomarker protein than the first antibody; (ii) detecting the presence of second antibody bound to the biomarker protein; and (iii) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (ii) detecting the presence of second antibody bound to the first antibody; and (iii) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is thalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is lenalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is pomalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• an array of probes for determining the levels of two or more biomarkers in a sample by hybridizing with one or more of the polynucleotides of the biomarkers under stringent condition wherein the biomarkers are each independently selected from biomarkers identified in Table 1 and/or Table 2, wherein the levels of the biomarkers are used to select a subject for treatment of a solid tumor with a treatment compound; predict or monitor the responsiveness of a subject to the treatment; or monitor the compliance of a subject with the treatment.
• an array of probes for determining the levels of two or more biomarkers in a sample by hybridizing with one or more of mRNAs of the biomarkers under stringent condition wherein the biomarkers are each independently selected from biomarkers identified in Table 1 and/or Table 2, wherein the levels of the biomarkers are used to select a subject for treatment of a solid tumor with a treatment compound; predict or monitor the responsiveness of a subject to the treatment; or monitor the compliance of a subject with the treatment.
• biomarkers are each independently selected from
• a panel of isolated biomarkers comprising two or more biomarkers, each of which is independently selected from Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZFP198.
• a panel of isolated biomarkers comprising two or more biomarkers, each of which is independently selected from AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ARHGAP19, ASNS, ASPM, ATP2B4, B4GALT3, BANK1, BCDIN3D, BLZF1, BMF, BST2, C10orf76, C19orf66, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CD36, CDC7, CDC A3, CENPF, CLN3, C N3, COROIB, CPNE2, CRBN, CSNK1A1, CSRP2, CT ND1, CTSH, DAPK2, DDX58, DHPS, DHX58, DLG2, DLGAP5, DOK3, DTX3L, ECT2, EFCAB4B, EHMT1 , EHMT2, EIF2AK2, EPB41L1 , EPCAM, ESRP1 , ETV6, EX
• SAMD9L SAMHD1 , SEC14L1 , SERPINH1 , SGOL1 , SGOL2, SLC03A1 , SLC04A1 ,
• SLFNl l SLFN13, SLFN5, SPl lO, SP140, SPN, SPR, STAPl , STATl , STAT2, TACC3, TAPl , TAX1BP3, THEMIS2, THTPA, TIMM8B, TNFAIP8L2, TNFSF8, TOP2A, TP53I3, TPX2, TREX1 , TRIB3, TRIM22, TTC39C, TXNIP, UBA7, UBE2L6, USP41 , VCL, VNN2, WIZ, WSB1 , WWC1 , ZBTB38, ZFP91 , ZMYM2, ZNF385B, ZNF581 and ZNF644.
• the solid tumors are sarcomas, carcinomas (epithelial tumors), melanomas, and glioblastomas.
• Exemplary solid tumors include, but not limited to, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g. , meningioma; glioma, e.g.
• astrocytoma oligodendroglioma, glioblastoma (GBM); medulloblastoma
• cervical cancer e.g., cervical adenocarcinoma
• colorectal cancer e.g., colon cancer, rectal cancer, colorectal adenocarcinoma
• gastric cancer e.g., stomach adenocarcinoma
• head and neck cancer e.g., head and neck squamous cell carcinoma
• oral cancer e.g., oral squamous cell carcinoma (OSCC)
• kidney cancer e.g., nephroblastoma a.k.a.
• liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
• lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
• neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2
• NF neurofibromatosis
• schwannomatosis neuroendocrine cancer
• GEP-NET gastroenteropancreatic neuroendoctrine tumor
• carcinoid tumor carcinoid tumor
• osteosarcoma ovarian cancer
• cystadenocarcinoma ovarian embryonal carcinoma, ovarian adenocarcinoma
• pancreatic cancer e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)
• prostate cancer e.g., prostate adenocarcinoma
• skin cancer e.g., squamous cell carcinoma (SCC), keratoacanthoma ( A), melanoma, basal cell carcinoma (BCC)
• soft tissue sarcoma e.g.
• the solid tumor is a liver cancer.
• the solid tumor is HCC.
• the solid tumor is a brain cancer.
• the solid tumor is GBM.
• kits for determining the level of a biomarker in a biological sample from a subject wherein the biomarker is selected from the group consisting of biomarkers identified in Table 1 and/or Table 2, and combinations thereof.
• the methods, arrays, probes, and kits provided herein are based, in part, on the discovery that a changed level, e.g., an increased level and/or a decreased level, of certain molecules (e.g. , mRNAs, cDNA, or proteins) in a biological sample can be utilized as biomarkers to predict responsiveness of a subject having or suspected to have a solid tumor to a treatment compound, e.g. , thalidomide, lenalidomide, pomalidomide, Compound A, or
• Compound B or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the methods provided herein are based on comparison of the level of one or more biomarkers in a biological sample from a subject having or suspected to have a solid tumor to a reference level of the biomarkers or the level of a control.
• the biomarker level is used to determine or to predict, for example, the likelihood of the subject's
• a treatment compound such as thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• FIGS. 1A-C show the relative protein abundance in the proteomics study in two cell lines, Focus and HAK-IAJ.
• FIG. 1A shows the relative protein abundance in the proteomics study using Focus cells.
• FIG. IB shows the relative protein abundance in the proteomics study using HAK-IAJ.
• FIG. 1C shows proteins commonly differentially abundant at 24 hours after treatment with Compound A in both Focus and HAK-IAJ cell lines.
• FIGS. 2A-B show the proteomics study results using a HCC cell line (Focus).
• FIG. 2 A shows the level of CRBN and ZFP91 in control plate and proteomic preparation (established) in 3D Focus cells treated with Compound A for various times.
• FIG. 2B shows the colony number and total colony area of control plates.
• FIGS. 3A-B show the proteomics study results using a HCC cell line (JHH4).
• FIG. 3 A shows the level of CRBN and ZFP91 in control plate and proteomic preparation (established) in 3D JHH4 cells treated with Compound A for various times.
• FIG. 3B shows the colony number and total colony area of control plates.
• FIGS. 4A-D show western blot analysis results using HCC cell lines (Focus and JHH4).
• FIG. 4 A shows the level of ZFP91 reduces in response to treatment with Compound A or Compound B in Focus cells.
• FIG. 4B shows the level of ZFP91 reduces in response to treatment with Compound A in Focus and JHH4 cell lines, and the level of CRBN increases in response to treatment with Compound A in Focus and JHH4 cell lines.
• FIG. 4C shows ZFP91 degradation induced by various doses of Compound A for various time periods in Focus and JHH4 cells.
• FIG.4D shows confirmation of ZFP91 being degraded in response to Compound A treatment using siRNAs.
• FIGS. 5A-D show results of compound treatment on ZFP91.
• FIG. 5A shows MG 132 and MLN block the reduction of the level of ZFP91 in response to Compound A treatment in HCC cell lines using western blot analysis.
• FIG. 5B shows Compound A accelerates ZFP91 degradation through proteasome -mediated degradation.
• FIGS. 5C-D show knocking down of CRBN reverses the effect of the treatment compounds on ZFP91 protein level.
• FIGS. 6A-B show results of compound treatment in Hep3B cells.
• FIG.6A shows that ZFP91 is down-regulated in response to treatment compounds in a CRBN dependent pathway in Hep3B cell lines.
• FIG.6B shows that Hep3B cells are sensitive to Compound B, but not to Compound A.
• FIGS. 7A-B show the results of Compound A treatment on ZFP91.
• FIG.7A shows that ZFP91 is down-regulated in response to treatment with Compound A or lenalidomide in a CRBN dependent pathway in U87 and SNB19 cells.
• FIG.7B shows Compound A inhibits U87 tumor growth, and the result of immunostaining assay demonstrating that Compound A degrades ZFP91 in U87 xenograft tissue.
• treat refers to alleviating or abrogating a disease, e.g., HCC or GBM, or one or more of the symptoms associated with the disease; or alleviating or eradicating the cause(s) of the disease itself.
• solid tumor refers to an abnormal mass of tissue. Solid tumors may be benign or malignant. A solid tumor grows in an anatomical site outside the bloodstream (in contrast, for example, to cancers of hematopoietic origin such as leukemias) and requires the formation of small blood vessels and capillaries to supply nutrients, etc. to the growing tumor mass. Solid tumors are named for the type of cells that form them. Non- limiting examples of solid tumors are sarcomas, carcinomas (epithelial tumors), melanomas, and glioblastomas.
• Exemplary solid tumors include, but are not limited to, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g., meningioma; glioma, e.g., astrocytoma, oligodendroglioma, glioblastomas; medulloblastoma), cervical cancer (e.g., cervical adenocarcinoma), colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma), gastric cancer (e.g.
• biliary cancer e.g., cholangiocarcinoma
• bladder cancer e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medull
• stomach adenocarcinoma gastrointestinal stromal tumor
• GIST gastrointestinal stromal tumor
• head and neck cancer e.g., head and neck squamous cell carcinoma
• oral cancer e.g., oral squamous cell carcinoma (OSCC)
• kidney cancer e.g., nephroblastoma a.k.a.
• liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
• lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), neuroblastoma, neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis), neuroendocrine cancer (e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g. , cystadenocarcinoma, ovarian embryonal carcinoma, ovarian
• GCP-NET gastroenteropancreatic neuroendoctrine tumor
• osteosarcoma ovarian cancer
• ovarian cancer e.g. , cystadenocarcinoma, ovarian embryonal carcinoma, ovarian
• pancreatic cancer e.g. , pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN)
• prostate cancer e.g., prostate adenocarcinoma
• skin cancer e.g., squamous cell carcinoma (SCC), keratoacanthoma ( A), melanoma, basal cell carcinoma (BCC)
• soft tissue sarcoma e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma, osteosarcoma).
• terapéuticaally effective amount of a compound refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of a disease, e.g., HCC or GBM, being treated.
• the term also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a biological molecule (e.g., a protein, enzyme, R A, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
• a biological molecule e.g., a protein, enzyme, R A, or DNA
• a therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of a disease, e.g., HCC or GBM.
• the term encompasses an amount that improves overall therapy, reduces, or avoids symptoms or causes of a disease, e.g., HCC or GBM, or enhances the therapeutic efficacy of another therapeutic agent.
• level refers to the amount, accumulation, or rate of a biomarker molecule.
• a level can be represented, for example, by the amount or the rate of synthesis of a massager RNA (mPvNA) encoded by a gene, the amount or the rate of synthesis of a polypeptide or protein encoded by a gene, or the amount or the rate of synthesis of a biological molecule accumulated in a cell or biological fluid.
• level refers to an absolute amount of a molecule in a sample or to a relative amount of the molecule, determined under steady-state or non-steady-state conditions.
• responsiveness or “responsive” when used in reference to a treatment refer to the degree of effectiveness of the treatment in lessening or decreasing the symptoms of a disease, e.g., HCC or GBM, being treated.
• increased responsiveness when used in reference to a treatment of a cell or a subject refers to an increase in the
• the increase in the effectiveness is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%>.
• an effective subject response refers to any increase in the therapeutic benefit to the patient.
• An “effective patient tumor response” can be, for example, a 5%, 10%>, 15%, 20%>, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,or 100% decrease in the rate of progress of the tumor.
• An “effective patient tumor response” can be, for example, a 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% decrease in the physical symptoms of a cancer.
• an “effective patient tumor response” can be, for example, a 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%,or 100% decrease in the size of a tumor.
• An “effective patient tumor response” can be, for example, a 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%), 90%,or 100%) decrease in the physical symptoms of a cancer or the tumor size.
• “effective patient tumor response” can also be, for example, a 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or more increase in the response of the patient, as measured by any suitable means, such as gene expression, cell counts, assay results, etc.
• predict generally means to determine or tell in advance.
• the term “predict” can mean that the likelihood of the outcome of the treatment can be determined at the outset, before the treatment has begun, or before the treatment period has progressed substantially.
• polypeptide refers to a polymer of two or more amino acids in a serial array, linked through one or more peptide bond(s).
• the term encompasses proteins, protein fragments, protein analogues, oligopeptides, and peptides.
• the amino acids of the polypeptide, protein, or peptide can be naturally occurring amino acids or synthetic amino acids (e.g., mimics of naturally occurring amino acids).
• the polypeptide, protein, or peptide can be made synthetically or purified from a biological sample.
• the polypeptide, protein, or peptide also encompasses modified
• polypeptides, proteins, and peptides e.g., a glycopolypeptide, glycoprotein, or glycopeptide; or a lipopolypeptide, lipoprotein, or lipopeptide.
• antibody refers to a polypeptide that specifically binds an epitope (e.g., an antigen).
• the term “antibody” is used herein in the broadest sense and covers fully assembled antibodies, antibody fragments which retain the ability to specifically bind to an antigen (e.g. , Fab, F(ab') 2 , Fv, and other fragments), single chain antibodies, diabodies, antibody chimeras, hybrid antibodies, bispecific antibodies, and humanized antibodies.
• antibody also covers both polyclonal and monoclonal antibodies.
• RNA nucleic acid molecule e.g., mRNA
• expression refers to the transcription from a gene to give an RNA nucleic acid molecule, e.g., mRNA, at least complementary in part to a region of one of the two nucleic acid strands of the gene.
• RNA nucleic acid molecule e.g., mRNA
• the term “expressed” or “expression” as used herein also refers to the translation from an RNA molecule to give a protein, a polypeptide or a portion thereof.
• a biological marker or "biomarker” is a substance whose detection indicates a particular biological state, such as, for example, the presence of cancer. In some embodiments, biomarkers can either be determined individually, or several biomarkers can be measured simultaneously. [0072] A “biomarker” can indicate a change in the level of mR A expression that may correlate with the risk or progression of a disease, or with the susceptibility of the disease to a given treatment.
• the biomarker is a nucleic acid, such as a mRNA or cDNA.
• a “biomarker” can indicate a change in the level of polypeptide or protein expression that may correlate with the risk, susceptibility to treatment, or progression of a disease.
• the biomarker can be a polypeptide or protein, or a fragment thereof.
• the relative level of specific proteins can be determined by methods known in the art. For example, antibody based methods, such as an immunoblot, enzyme-linked immunosorbent assay (ELISA), or other methods can be used.
• An mRNA that is "upregulated” is generally increased upon a given treatment or condition.
• An mRNA that is “downregulated” generally refers to a decrease in the level of expression of the mRNA in response to a given treatment or condition. In some situations, the mRNA level can remain unchanged upon a given treatment or condition.
• An mRNA from a patient sample can be "upregulated” when treated with a drug, as compared to a non-treated control.
• This upregulation can be, for example, an increase of about 5%, 10%, 20%>, 30%>, 40%>, 50%, 60%, 70%, 90%, 100%, 200%, 300%, 500%, 600%, 700%, 800%, 900%, 1,000%, 1,500%, 2,000%, 2,500%, 3,00%, 3,500%, 4,000%, 4,500%, 5,000% or more of the comparative control mRNA level.
• an mRNA can be "downregulated", or expressed at a lower level, in response to administration of certain compounds or other agents.
• a downregulated mRNA can be, for example, present at a level of about 99%, 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10%, 5%, 3%, 1% or less of the
• the level of a polypeptide or protein biomarker from a patient sample can be increased when treated with a drug, as compared to a non-treated control.
• This increase can be about 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, 700%, 1,000%, 1 ,500%, 2,000%, 2,500%, 3,000%, 3,500%, 4,000%, 4,500%, 5,000% or more of the comparative control protein level.
• the level of a protein biomarker can be decreased in response to administration of certain compounds or other agents. This decrease can be, for example, present at a level of about 99%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%), 20%), 10%), 5%o, 3%o, 1%) or less of the comparative control protein level.
• determining means determining if an element is present or not.
• evaluating means determining if an element is present or not.
• assessing means determining if an element is present or not.
• determinations can include determining the amount of something present, as well as determining whether it is present or absent.
• nucleic acid and “polynucleotide” are used interchangeably herein to refer to a polymer of nucleotides, e.g., deoxyribonucleotides or ribonucleotides, or compounds, which can hybridize with a naturally occurring nucleic acid in a sequence specific manner analogous to that of two naturally occurring nucleic acids, e.g., participating in Watson-Crick base pairing interactions.
• bases are synonymous with “nucleotides” (or “nucleotide”), i.e., the monomer subunit of a polynucleotide.
• nucleoside and nucleotide are intended to include those moieties that contain not only the known purine and pyrimidine bases, but also other heterocyclic bases that have been modified. Such modifications include methylated purines or pyrimidines, acylated purines or pyrimidines, alkylated riboses or other heterocycles.
• the terms “nucleoside” and “nucleotide” include those moieties that contain not only
• Modified nucleosides or nucleotides also include modifications on the sugar moiety, e.g., wherein one or more of the hydroxyl groups are replaced with halogen atoms or aliphatic groups, or are functionalized as ethers, amines, or the like.
• analogue of a "nucleic acid” or “polynucleotide” refers to a molecule having a structural feature that is recognized in the literature as being a mimetic, derivative, having an analogous structure, or other like terms, and includes, for example, a polynucleotide incorporating a non-natural nucleotide, a nucleotide mimetic such as a 2'- modified nucleoside, peptide nucleic acid, oligomeric nucleoside phosphonate, and any polynucleotide that has added substituent groups, such as protecting groups or linking moieties.
• a first polynucleotide and a second polynucleotide are complementary if they bind to each other in a hybridization assay under stringent conditions, e.g., if they produce a given or detectable level of signal in a hybridization assay.
• Portions of polynucleotides are complementary to each other if they follow conventional base-pairing rules, e.g., A pairs with T (or U) and G pairs with C, although small regions (e.g. less than about 3 bases) of mismatch, insertion, or deleted sequence may be present.
• sequence identity in the context of two nucleic acid sequences refers to the residues in the two sequences which are the same when aligned for maximum correspondence over a specified comparison window, and can take into consideration additions, deletions and substitutions.
• substantially identical in their various grammatical forms in the context of polynucleotides generally means that a polynucleotide comprises a sequence that has a desired identity, for example, at least 60%, at least 70%>, at least 80%>, at least 90%> and at least 95% sequence identity, compared to a reference sequence. Another indication that nucleotide sequences are substantially identical is if two molecules hybridize to each other under stringent conditions.
• bound can be used herein to indicate direct or indirect attachment.
• bound (or “bonded”) may refer to the existence of a chemical bond directly joining two moieties or indirectly joining two moieties (e.g., via a linking group or any other intervening portion of the molecule).
• the chemical bond may be a covalent bond, an ionic bond, a coordination complex, hydrogen bonding, van der Waals interactions, or hydrophobic stacking, or may exhibit characteristics of multiple types of chemical bonds.
• “bound” includes embodiments where the attachment is direct and also embodiments where the attachment is indirect.
• isolated and purified refer to isolation of a substance (such as mR A or protein) such that the substance comprises a substantial portion of the sample in which it resides, i.e., greater than the substance is typically found in its natural or un-isolated state.
• a substantial portion of the sample comprises, e.g., greater than about 1%, greater than about 2%, greater than about 5%, greater than about 10%, greater than about 20%, greater than about 50%), or more, usually up to about 90%> to 100%) of the sample.
• a sample of isolated mRNA can typically comprise at least about 1% total mRNA.
• Techniques for purifying polynucleotides include, for example, gel electrophoresis, ion- exchange chromatography, affinity chromatography, flow sorting, and sedimentation according to density.
• biological sample refers to a sample obtained from a biological subject, including a sample of biological tissue or fluid origin, obtained, reached, or collected in vivo or in situ.
• a biological sample also includes samples from a region of a biological subject containing precancerous or cancer cells or tissues. Such samples can be, but are not limited to, organs, tissues, fractions and cells isolated from a mammal.
• Exemplary biological samples include, but are not limited to, cell lysate, a cell culture, a cell line, a tissue, oral tissue, gastrointestinal tissue, an organ, an organelle, a biological fluid, a blood sample, a urine sample, a skin sample, and the like.
• biological samples include, but are not limited to, whole blood, partially purified blood, PBMCs, tissue biopsies, and the like.
• analyte refers to a known or unknown component of a sample.
• capture agent refers to an agent that binds an mRNA or protein through an interaction that is sufficient to permit the agent to bind and concentrate the mRNA or protein from a homogeneous mixture.
• probe refers to a capture agent that is directed to a specific target mRNA biomarker sequence. Accordingly, each probe of a probe set has a respective target mRNA biomarker.
• a probe/target mRNA duplex is a structure formed by hybridizing a probe to its target mRNA biomarker.
• nucleic acid probe or “oligonucleotide probe” refers to a nucleic acid capable of binding to a target nucleic acid of complementary sequence, such as the mRNA biomarkers provided herein, through one or more types of chemical bonds, usually through complementary base pairing, usually through hydrogen bond formation.
• a probe may include natural ⁇ e.g., A, G, C, or T) or modified bases (7-deazaguanosine, inosine, etc.).
• the bases in a probe may be joined by a linkage other than a phosphodiester bond, so long as it does not interfere with hybridization.
• probes may bind target sequences lacking complete complementarity with the probe sequence depending upon the stringency of the hybridization conditions.
• the probes are preferably directly labeled with isotopes, for example, chromophores, lumiphores, chromogens, or indirectly labeled with biotin to which a streptavidin complex may later bind.
• isotopes for example, chromophores, lumiphores, chromogens, or indirectly labeled with biotin to which a streptavidin complex may later bind.
• stringent assay conditions refers to conditions that are compatible to produce binding pairs of nucleic acids, e.g., probes and target mRNAs, of sufficient
• stringent assay conditions generally refers to the combination of hybridization and wash conditions.
• a "label” or a “detectable moiety” in reference to a nucleic acid refers to a composition that, when linked with a nucleic acid, renders the nucleic acid detectable, for example, by spectroscopic, photochemical, biochemical, immunochemical, or chemical means.
• Exemplary labels include, but are not limited to, radioactive isotopes, magnetic beads, metallic beads, colloidal particles, fluorescent dyes, enzymes, biotin, digoxigenin, haptens, and the like.
• a "labeled nucleic acid or oligonucleotide probe” is generally one that is bound, either covalently, through a linker or a chemical bond, or noncovalently, through ionic bonds, van der Waals forces, electrostatic attractions, hydrophobic interactions, or hydrogen bonds, to a label such that the presence of the nucleic acid or probe can be detected by detecting the presence of the label bound to the nucleic acid or probe.
• PCR polymerase chain reaction
• sequence information from the ends of the region of interest or beyond needs to be available, such that oligonucleotide primers can be designed; these primers will be identical or similar in sequence to opposite strands of the template to be amplified.
• the 5' terminal nucleotides of the two primers may coincide with the ends of the amplified material.
• PCR can be used to amplify specific RNA sequences, specific DNA sequences from total genomic DNA, and cDNA transcribed from total cellular RNA, bacteriophage or plasmid sequences, etc. See generally Mullis et al., Cold Spring Harbor Symp. Quant. Biol, 51 : 263 (1987); Erlich, ed., PCR Technology, (Stockton Press, NY, 1989).
• cycle number refers to the PCR cycle number at which the fluorescence level passes a given set threshold level.
• the CT measurement can be used, for example, to approximate levels of mRNA in an original sample.
• the CT measurement is often used in terms of "dCT” or the “difference in the CT” score, when the CT of one nucleic acid is subtracted from the CT of another nucleic acid.
• “approximately” means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%), or 0.05%) of a given value or range.
• a biological marker or "biomarker” is a substance, the change and/or the detection of which indicates a particular biological state, such as, for example, the responsiveness of a disease, e.g., HCC or GBM, to a given treatment, e.g., a treatment by a treatment compound, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a treatment compound e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the present application is based, in part, on the finding that the levels of certain proteins change in response to treatment compound, e.g., as shown in the proteomics study in the Examples.
• certain proteins upregulated in response to Compound A treatment include Nestin, KAT1/CCBL1, and WIBG
• certain proteins downregulated in response to Compound A treatment include MVP, PARP4, ZFP91, and ZNF198.
• the biomarker provided herein is selected from a group consisting of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, and WIBG.
• the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198.
• biomarkers provided herein include proteins selected from AFINAK, ALOX5, AMPD3, ANXA4, ANXA6, ARHGAP19, ASNS, ASPM, ATP2B4, B4GALT3, BANK1, BCDIN3D, BLZF1, BMF, BST2, C10orf76, C19orf66, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CD36, CDC7, CDC A3, CENPF, CLN3, CNN3, COROIB, CPNE2, CRBN,
• the biomarker is a protein selected from AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ATP2B4, BMF, BST2, C10orf76, C19orf66, CD36, CLN3, CNN3, COROIB, CPNE2, CRBN, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHX58, DLG2, DTX3L, EIF2AK2,EPB41L1, ETV6, EXTL2, F13A1, FAM65B, FCGR2B, FES, FMNL3, GBP1, GMFG, GMPR, HIP1, HLA-B, HLA-DMA, HPSE, ID3, IFI35, IFIH1, IFIT1, IFIT3, IFIT5, IFITM2, IL4I1, IRF7, IRF9, ISG15, ISG20, ITGB7, JAK3, LAP3, LGALS1,
• the biomarker is a protein selected from ARHGAP19, ASNS, ASPM, B4GALT3, BANK1, BCDIN3D, BLZF1, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CDC7, CDC A3, CENPF, CSNK1A1DHPS, DLGAP5, DOK3, ECT2, EFCAB4B, EHMT1, EHMT2, EPCAM, ESRP1, FAM195A, FBRSL1, FHOD1, FIGNL1, GPT2, GRAMD1A, GRAMD1B, GRPEL2, HJURP, HMCES, HMMR, HOXC4, ICAM2, IKZF1, IKZF3, IRS2, KIF18B, KIF22, KIF2C, LIPG, LPXN, MINA, MIS18BP1, NEILI, NFKBID, NPIPB5, OMAl, ORC6, PARVB, PBK, PDE6D, PKMYT1, PLK1,
• the biomarker is AF1NAK. In some embodiments, the biomarker is ALOX5. In one embodiment, the biomarker is AMPD3. In another embodiment, the biomarker is ANXA4. In some embodiments, the biomarker is ANXA6. In one embodiment, the biomarker is ARHGAP19. In another embodiment, the biomarker is ASNS. In some
• the biomarker is ASPM. In one embodiment, the biomarker is ATP2B4. In another embodiment, the biomarker is B4GALT3. In some embodiments, the biomarker is BANK1. In one embodiment, the biomarker is BCDIN3D. In another embodiment, the biomarker is BLZF1. In some embodiments, the biomarker is BMF. In one embodiment, the biomarker is BST2. In another embodiment, the biomarker is C10orf76. In some embodiments, the biomarker is C19orf66. In one embodiment, the biomarker is CA2. In another embodiment, the biomarker is CA8. In some embodiments, the biomarker is CAMSAP3. In one embodiment, the biomarker is CCDC69.
• the biomarker is CCNB1. In some embodiments, the biomarker is CD36. In one embodiment, the biomarker is CDC7. In another embodiment, the biomarker is CDC A3. In some embodiments, the biomarker is CENPF. In one embodiment, the biomarker is CLN3. In another embodiment, the biomarker is CNN3. In some embodiments, the biomarker is COROIB. In one embodiment, the biomarker is CPNE2. In another embodiment, the biomarker is CRBN. In some embodiments, the biomarker is
• the biomarker is CSRP2. In another embodiment, the biomarker is CTNND1. In some embodiments, the biomarker is CTSH. In one embodiment, the biomarker is DAPK2. In another embodiment, the biomarker is DDX58. In some embodiments, the biomarker is DHPS. In one embodiment, the biomarker is DHX58. In another embodiment, the biomarker is DLG2. In some embodiments, the biomarker is DLGAP5. In one embodiment, the biomarker is DOK3. In another embodiment, the biomarker is DTX3L. In some embodiments, the biomarker is ECT2. In one embodiment, the biomarker is EFCAB4B. In another
• the biomarker is EHMT1. In some embodiments, the biomarker is EHMT2. In one embodiment, the biomarker is EIF2AK2. In another embodiment, the biomarker is EPB41L1. In some embodiments, the biomarker is EPCAM. In one embodiment, the biomarker is ESRP1. In another embodiment, the biomarker is ETV6. In some embodiments, the biomarker is EXTL2. In one embodiment, the biomarker is F13A1. In another embodiment, the biomarker is FAM195A. In some embodiments, the biomarker is FAM65B. In one embodiment, the biomarker is
• the biomarker is FCGR2B. In some embodiments, the biomarker is FES. In one embodiment, the biomarker is FHOD1. In another embodiment, the biomarker is FIGNL1. In some embodiments, the biomarker is FMNL3. In one embodiment, the biomarker is GBP1. In another embodiment, the biomarker is GMFG. In some embodiments, the biomarker is GMPR. In one embodiment, the biomarker is GPT2. In another embodiment, the biomarker is GRAMD1A. In some embodiments, the biomarker is GRAMD1B. In one embodiment, the biomarker is GRPEL2. In another embodiment, the biomarker is HIP1. In some embodiments, the biomarker is HJURP.
• the biomarker is HLA-B. In another embodiment, the biomarker is HLA-DMA. In some embodiments, the biomarker is HMCES. In one embodiment, the biomarker is HMMR. In another embodiment, the biomarker is HOXC4. In some embodiments, the biomarker is HPSE. In one embodiment, the biomarker is ICAM2. In another embodiment, the biomarker is ID3. In some embodiments, the biomarker is IFI35. In one embodiment, the biomarker is IFIH1. In another embodiment, the biomarker is IFIT1. In some embodiments, the biomarker is IFIT3. In one embodiment, the biomarker is IFIT5. In another embodiment, the biomarker is IFITM2.
• the biomarker is IKZF1. In one embodiment, the biomarker is IKZF3. In another embodiment, the biomarker is IL4I1. In some embodiments, the biomarker is IRF7. In one embodiment, the biomarker is IRF9. In another embodiment, the biomarker is IRS2. In some embodiments, the biomarker is ISG15. In one embodiment, the biomarker is ISG20. In another embodiment, the biomarker is ITGB7. In some embodiments, the biomarker is JAK3. In one embodiment, the biomarker is KIF18B. In another embodiment, the biomarker is KIF22. In some embodiments, the biomarker is KIF2C. In one embodiment, the biomarker is LAP3.
• the biomarker is LGALS1. In some embodiments, the biomarker is LGALS3BP. In one embodiment, the biomarker is LIMD1. In another embodiment, the biomarker is LIPG. In some embodiments, the biomarker is LPXN. In one embodiment, the biomarker is MAN2A2. In another embodiment, the biomarker is MARCKS. In some embodiments, the biomarker is MFI2. In one embodiment, the biomarker is MGARP. In another embodiment, the biomarker is MINA. In some embodiments, the biomarker is MIS18BP1. In one embodiment, the biomarker is MOV 10. In another embodiment, the biomarker is MPP7. In some embodiments, the biomarker is MUC1.
• the biomarker is MX1. In another embodiment, the biomarker is MX2. In some embodiments, the biomarker is MYOIG. In one embodiment, the biomarker is NCF2. In another embodiment, the biomarker is NEIL1. In some embodiments, the biomarker is NFKBID. In one embodiment, the biomarker is NME3. In another embodiment, the biomarker is NMI. In some embodiments, the biomarker is NPIPB5. In one embodiment, the biomarker is NT5C3A. In another embodiment, the biomarker is OAS1. In some embodiments, the biomarker is OAS2. In one embodiment, the biomarker is OAS3. In another embodiment, the biomarker is OMAl .
• the biomarker is ORC6. In one embodiment, the biomarker is PARP14. In another embodiment, the biomarker is PARP9. In some embodiments, the biomarker is PARVB. In one embodiment, the biomarker is PBK. In another embodiment, the biomarker is PBXIPI . In some embodiments, the biomarker is PDE6D. In one embodiment, the biomarker is PKMYT1. In another embodiment, the biomarker is PLD4. In some embodiments, the biomarker is PLEKHOl . In one embodiment, the biomarker is PLK1. In another embodiment, the biomarker is PLSCR1. In some
• the biomarker is PLXNB2. In one embodiment, the biomarker is PODXL. In another embodiment, the biomarker is PODXL2. In some embodiments, the biomarker is POLE2. In one embodiment, the biomarker is POMP. In another embodiment, the biomarker is PPFIBP1. In some embodiments, the biomarker is PRDM15. In another embodiment, the biomarker is PRNP. In one embodiment, the biomarker is PTAFR. In another embodiment, the biomarker is PTMS. In some embodiments, the biomarker is PTTG1. In one embodiment, the biomarker is PYROXD1. In another embodiment, the biomarker is QPRT. In some
• the biomarker is RAB13. In one embodiment, the biomarker is RASA4B. In another embodiment, the biomarker is RASSF6. In some embodiments, the biomarker is RCN1. In one embodiment, the biomarker is RGCC. In another embodiment, the biomarker is RGS1. In some embodiments, the biomarker is RGS2. In one embodiment, the biomarker is RNF213. In another embodiment, the biomarker is S100A13. In some embodiments, the biomarker is SAMD9L. In one embodiment, the biomarker is SAMHD1. In another embodiment, the biomarker is SEC14L1. In some embodiments, the biomarker is SERPINHI . In one embodiment, the biomarker is SGOL1. In another embodiment, the biomarker is SGOL2. In some embodiments, the biomarker is SERPINHI . In one embodiment, the biomarker is SGOL1. In another embodiment, the biomarker is SGOL2. In some
• the biomarker is SLC03A1. In one embodiment, the biomarker is SLC04A1. In another embodiment, the biomarker is SLFN11. In some embodiments, the biomarker is
• the biomarker is SLFN13. In one embodiment, the biomarker is SLFN5. In another embodiment, the biomarker is SP110. In some embodiments, the biomarker is SP140. In one embodiment, the biomarker is SPN. In another embodiment, the biomarker is SPR. In some embodiments, the biomarker is STAP1. In one embodiment, the biomarker is STAT1. In another embodiment, the biomarker is STAT2. In some embodiments, the biomarker is TACC3. In one embodiment, the biomarker is TAP1. In another embodiment, the biomarker is TAX1BP3. In some embodiments, the biomarker is THEMIS2. In one embodiment, the biomarker is THTPA. In another embodiment, the biomarker is TIMM8B.
• the biomarker is TNFAIP8L2. In one embodiment, the biomarker is TNFSF8. In another embodiment, the biomarker is TOP2A. In some embodiments, the biomarker is TP53I3. In one embodiment, the biomarker is TPX2. In another embodiment, the biomarker is TREX1. In some embodiments, the biomarker is TRIB3. In one embodiment, the biomarker is TRIM22. In another embodiment, the biomarker is TTC39C. In some embodiments, the biomarker is TXNIP. In one embodiment, the biomarker is UBA7. In another embodiment, the biomarker is UBE2L6. In some embodiments, the biomarker is USP41.
• the biomarker is VCL. In another embodiment, the biomarker is VNN2. In some embodiments, the biomarker is WIZ. In one embodiment, the biomarker is WSB1. In another embodiment, the biomarker is WWC1. In some embodiments, the biomarker is ZBTB38. In one embodiment, the biomarker is ZFP91. In another embodiment, the biomarker is ZMYM2. In some embodiments, the biomarker is ZNF385B. In one embodiment, the biomarker is ZNF581. In another embodiment, the biomarker is ZNF644.
• the biomarkers provided herein are upregulated in response to compound treatment.
• the biomarker upregulated in response to compound treatment is selected from proteins in Table 1.
• the biomarker upregulated in response to compound treatment is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG.
• the biomarker upregulated in response to compound treatment is Nestin.
• the biomarker upregulated in response to compound treatment is KATl/CCBLl .
• the biomarker upregulated in response to compound treatment is WIBG.
• the biomarker selected from a group consisting of Nestin, KATl/CCBLl, and WIBG is upregulated in response to Compound A treatment.
• the biomarkers provided herein are downregulated in response to compound treatment.
• the biomarker downregulated in response to compound treatment is selected from proteins in Table 2.
• the biomarker downregulated in response to compound treatment is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198.
• the biomarker downregulated in response to compound treatment is MVP.
• the biomarker downregulated in response to compound treatment is PARP4.
• the biomarker downregulated in response to compound treatment is ZFP91.
• the biomarker downregulated in response to compound treatment is ZNF198.
• the biomarker selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198 is downregulated in response to Compound A treatment.
• the present disclosure is also based, in part, on the discovery that ZFP91 is down- regulated in solid tumor cell lines, e.g., HCC or GBM, in response to a treatment with treatment compounds provided herein.
• the biomarker is ZFP91.
• ZFP91 zinc finger protein (ZFP91) encodes a 63.4 kDa nuclear protein with structural motifs characteristic of transcription factor, and it is expressed ubiquitously in various cell types and is known to be highly conservative. Paschke et al., Pathol Oncol Res., 2013, 20:453-459.
• ZFP91 is recognized as an atypical E3 ubiquitin-protein ligase, and mediates a K63-linked
• ZFP91 has implications in various cancers. For example, it has been shown that ZFP91 expression is upregulated in mononuclear cells from patients with acute myelogenous leukemia (AML) and in many neoplastic blood cell lines. In addition, the function of ZFP91 has been shown to relate to cell apoptosis rate. Id. Furthermore, ZFP91 has been shown to interact with ARF tumor suppressor (cyclin-dependent kinase inhibitor 2A, isoform 4), the von Hippel-Lindau tumor suppressor (pVHL) and the hypoxia inducible factor- la (HIF-l ). In some embodiments, the biomarker is an isoform of ZFP91 protein.
• ARF tumor suppressor cyclin-dependent kinase inhibitor 2A, isoform 4
• pVHL von Hippel-Lindau tumor suppressor
• HIF-l hypoxia inducible factor- la
• the biomarker is an isoform of ZFP91 protein.
• the present disclosure is also based in part on the discovery that Cereblon (CRBN) is up-regulated in solid tumor cell lines, e.g., HCC or GBM, in response to a treatment with treatment compounds provided herein.
• the biomarker is CRBN.
• CRBN is a 442-amino acid protein conserved from plant to human.
• the CRBN gene has been identified as a candidate gene of an autosomal recessive nonsyndromic mental retardation (ARNSMR). See Higgins, J.J. et al. , Neurology, 2004, 63 : 1927- 1931.
• CRBN was initially characterized as an RGS -containing novel protein that interacted with a calcium- activated potassium channel protein (SLOl) in the rat brain, and was later shown to interact with a voltage-gated chloride channel (CIC-2) in the retina with AMPK7 and DDBl .
• SLOl calcium- activated potassium channel protein
• CIC-2 voltage-gated chloride channel
• DDB1 was originally identified as a nucleotide excision repair protein that associates with damaged DNA binding protein 2 (DDB2).
• DDB1 also appears to function as a component of numerous distinct DCX (DDBl-CUL4-X-box) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
• CRBN has also been identified as a target for the development of therapeutic agents for diseases of the cerebral cortex. See WO 2010/137547 Al .
• the biomarker is an isoform of CRBN.
• the biomarker is an mRNA of Nestin, KATl/CCBLl, WIBG, MVP, PARP4, ZFP91, ZNF198, or a combination thereof.
• the biomarker is an mRNA of Nestin, KATl/CCBLl, and WIBG.
• the biomarker is an mRNA of MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is an mRNA of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ARHGAP19, ASNS, ASPM, ATP2B4, B4GALT3, BANK1, BCDIN3D, BLZF1, BMF, BST2, C10orf76, C19orf66, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CD36, CDC7, CDC A3, CENPF, CLN3, CNN3, COROIB, CPNE2, CRBN, CSNK1A1, CSRP2, CTNNDl, CTSH, DAPK2, DDX58, DHPS, DHX58, DLG2, DLGAP5, DOK3, DTX3L, ECT2, EFCAB4B, EHMT1, EHMT2, EIF2AK2, EPB41L1, EPCAM, ESRP1, ETV6, EXTL2, F13A1, FAM195A, FAM65B, FBRSL1,
• the biomarker is an mRNA of AHNAK, ALOX5 , AMPD3 , ANXA4, ANXA6, ATP2B4, BMF, BST2, C10orf76, C19orf66, CD36, CLN3, CNN3,
• COROIB COROIB, CPNE2, CRBN, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHX58, DLG2, DTX3L, EIF2AK2,EPB41L1, ETV6, EXTL2, F13A1, FAM65B, FCGR2B, FES, FMNL3, GBP1, GMFG, GMPR, HIP1, HLA-B, HLA-DMA, HPSE, ID3, IFI35, IFIH1, IFIT1, IFIT3, IFIT5, IFITM2, IL4I1, IRF7, IRF9, ISG15, ISG20, ITGB7, JAK3, LAP3, LGALS1,
• the biomarker is an mRNA of ARHGAP19, ASNS, ASPM, B4GALT3, BANKl, BCDIN3D, BLZFl, CA2, CA8, CAMSAP3, CCDC69, CCNBl, CDC7, CDC A3, CENPF, CSNK1A1DHPS, DLGAP5, DOK3, ECT2, EFCAB4B, EHMT1, EHMT2, EPCAM, ESRP1, FAM195A, FBRSL1, FHOD1, FIGNL1, GPT2, GRAMD1A, GRAMD1B, GRPEL2, HJURP, HMCES, HMMR, HOXC4, ICAM2, IKZF1, IKZF3, IRS2, KIF18B, KIF22, KIF2C, LIPG, LPXN, MINA, MIS18BP1, NEILI, NFKBID, NPIPB5, OMAl, ORC6, PARVB, PBK, PDE6D, PKMYT
• the biomarker is an mRNA of CRBN. In another specific embodiment, the biomarker is an mRNA of Nestin. In another specific embodiment, the biomarker is an mRNA of KATl/CCBLl . In another specific embodiment, the biomarker is an mRNA of WIBG. In another specific embodiment, the biomarker is an mRNA of MVP. In another specific embodiment, the biomarker is an mRNA of PARP4. In another specific embodiment, the biomarker is an mRNA of ZNF198.
• the biomarker is a cDNA of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ARHGAP19, ASNS, ASPM, ATP2B4, B4GALT3, BANK1, BCDIN3D, BLZF1, BMF, BST2, C10orf76, C19orf66, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CD36, CDC7, CDC A3, CENPF, CLN3, CNN3, COROIB, CPNE2, CRBN, CSNK1A1, CSRP2, CTNNDl, CTSH, DAPK2, DDX58, DHPS, DHX58, DLG2, DLGAP5, DOK3, DTX3L, ECT2, EFCAB4B, EHMTl, EHMT2, EIF2AK2, EPB41L1, EPCAM, ESRPl, ETV6, EXTL2, F13A1, FAM195A, FAM65B, F
• the biomarker is a cDNA of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ATP2B4, BMF, BST2, C10orf76, C19orf66, CD36, CLN3, CNN3,
• COROIB COROIB, CPNE2, CRBN, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHX58, DLG2, DTX3L, EIF2AK2,EPB41L1, ETV6, EXTL2, F13A1, FAM65B, FCGR2B, FES, FMNL3, GBP1, GMFG, GMPR, HIP1, HLA-B, HLA-DMA, HPSE, ID3, IFI35, IFIH1, IFIT1, IFIT3, IFIT5, IFITM2, IL4I1, IRF7, IRF9, ISG15, ISG20, ITGB7, JAK3, LAP3, LGALS1,
• the biomarker is a cDNA of ARHGAP19, ASNS, ASPM, B4GALT3, BANKl, BCDIN3D, BLZFl, CA2, CA8, CAMSAP3, CCDC69, CCNBl, CDC7, CDC A3, CENPF, CSNK1A1DHPS, DLGAP5, DOK3, ECT2, EFCAB4B, EHMT1, EHMT2, EPCAM, ESRP1, FAM195A, FBRSL1, FHOD1, FIGNL1, GPT2, GRAMD1A, GRAMD1B, GRPEL2, HJURP, HMCES, HMMR, HOXC4, ICAM2, IKZFl, IKZF3, IRS2, KIF18B, KIF22, KIF2C, LIPG, LPXN, MINA, MIS18BP1, NEILI , NFKBID, NPIPB5, OMAl, ORC6, PARVB, PBK, PDE6D, P
• the biomarker is a cDNA of ZFP91. In another specific embodiment, the biomarker is a cDNA of CRBN. In certain embodiments, the biomarker is a cDNA of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, ZNF198, or a combination thereof. In certain embodiments, the biomarker is a cDNA of Nestin, KATl/CCBLl, and WIBG. In certain embodiments, the biomarker is a cDNA of MVP, PARP4, ZFP91, and
• the biomarker is a cDNA of Nestin. In another specific embodiment, the biomarker is a cDNA of KATl/CCBLl . In another specific embodiment, the biomarker is a cDNA of WIBG. In another specific embodiment, the biomarker is a cDNA of MVP. In another specific embodiment, the biomarker is a cDNA of PARP4. In another specific embodiment, the biomarker is a cDNA of ZNF198.
• the level of the biomarker provided herein correlates with or is indicative of the responsiveness of a disease (e.g., HCC or GBM) to a treatment, e.g., a treatment by a treatment compound, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a disease e.g., HCC or GBM
• a treatment compound e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the biomarker is an mR A. In other embodiments, the biomarker is a cDNA. The level of the biomarker can be determined using the methods provided herein.
• the biomarker is a protein.
• a biomarker is a protein.
• the level of the biomarker can be measured by determining the protein level, the mRNA level, or the enzymatic activity of the biomarker.
• the level of the biomarker can be determined using the methods provided herein.
• the reference level can be determined by a plurality of methods. In some
• the reference level is one that a treatment decision is made based on whether a subject having or suspected of having a solid tumor, e.g., HCC or GBM, has the level of the biomarker above the reference level. Subjects who have a level of the biomarker higher than the reference level have a different probability of responsiveness to the treatment than subjects who have a level of the biomarker lower than the reference level.
• the reference level is measured simultaneously with the biological sample from the subject. In some embodiments, the reference level is predetermined.
• the reference level is determined from a sample from the same subject that contains no solid tumor cells. In other embodiments, the reference level is determined from a sample from a group of subjects that contains no solid tumor cells. In yet other embodiments, the reference level is determined from a sample from a group of subjects who do not have the solid tumor.
• An increased level or a decreased level of the biomarker correlates positively with increased responsiveness of the subject to a treatment by a treatment compound, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a treatment compound e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the control sample is a sample containing no solid tumor cells from the same subject. In other embodiments, the control sample is a sample of liver cells containing no solid tumor cells from the same subject. In other embodiments, the control sample is a sample containing no solid tumor cells from a group of subjects. In other embodiments, the control sample is a sample of liver cells containing no solid tumor cells from a group of subjects. In yet other embodiments, the control sample is a sample from a subject having no solid tumor. In yet other embodiments, the control sample is a sample of liver cells from a subject having no solid tumor. In yet other embodiments, the control sample is a sample from a group of subjects having no solid tumor.
• control sample is a sample of liver cells from a group of subjects having no solid tumor.
• An increased or a decreased level of the one or more biomarkers as compared with the level of the control sample correlates positively with increased responsiveness of the subject to a treatment by a treatment compound, e.g.,
• the reference is prepared by using a second tumor cell not treated with the compound.
• the reference is prepared by using a second sample obtained from the subject prior to administration of the treatment compound to the patient; and wherein the second sample is from the same source as the sample.
• the reference is prepared by using a second sample obtained from a healthy subject not having the solid tumor; and wherein the second sample is from the same source as the sample.
• the biomarkers provided herein are determined individually. In other embodiments, two or more of the biomarkers provided herein are determined
• the level of a biomarker nucleic acid or polypeptide provided herein is measured in a biological sample from a subject, e.g., a HCC or a GBM cell containing- sample from the subject.
• an affinity binding assay is used to measure the level of the biomarker polypeptide.
• the affinity binding assays that are applicable for use in the methods provided herein include both soluble and solid phase assays.
• a soluble phase affinity binding assay is immunoprecipitation using a biomarker binding agent, e.g., an antibody reactive with the biomarker polypeptide.
• a biomarker binding agent e.g., an antibody reactive with the biomarker polypeptide.
• solid phase affinity binding assays include immunohistochemical binding assays and
• immunoaffinity binding assays examples include, but are not limited to, immunohistochemistry methods, immunoblot methods, ELISA and
• An antibody useful in the methods provided herein includes a polyclonal and monoclonal antibodies.
• An antibody useful in the methods provided herein includes naturally occurring antibodies as well as non-naturally occurring antibodies, e.g., single chain antibodies, chimeric antibodies, bifunctional antibodies, humanized antibodies, and antigen-binding fragments thereof.
• the biological sample can be liver tissue or a fluid such as blood, serum, or urine.
• the sample of cells from a subject is obtained via biopsy. Once a level of a biomarker is determined, this value can be correlated with clinical data on the subject from whom the sample is derived, e.g., the responsiveness of a subject to a given treatment.
• the sample of cells from a subject is obtained via biopsy.
• the level of only one of the biomarkers is monitored. In other embodiments, the levels of two or more of the biomarkers are monitored simultaneously.
• a solid tumor e.g., HCC or GBM
• a given treatment e.g., a treatment by a treatment compound, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof
• the levels of these biomarkers may be used for identifying a subject having a solid tumor, e.g., HCC or GBM, for the treatment by a treatment compound provided herein.
• a method for identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound.
• a method of identifying a subject having a solid tumor who is likely to be responsive to a treatment compound comprising:
• biomarker determining the level of a biomarker in the sample from the subject, wherein the biomarker is selected from the group consisting of biomarkers identified in Table 1 and/or Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor who is likely to be responsive to a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM. [00131] in another aspect, provided herein is a method of identifying a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the methods provided herein are coupled with a treatment by a treatment compound provided herein, e.g., thalidomide, lenalidomide, pomalidomide,
• a method of treating a solid tumor e.g., HCC or GBM.
• a method of treating a solid tumor comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and/or Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM. [00134] in another aspect, provided herein is a method of treating a solid tumor, e.g., HCC or GBM, comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• biomarker is selected from the group consisting of biomarkers identified in Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. [00137] In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6,
• SAMD9L SAMHD1, SEC14L1, SERPINH1, SGOL1, SGOL2, SLC03A1, SLC04A1,
• SLFNl l SLFN13, SLFN5, SPl lO, SP140, SPN, SPR, STAPl, STATl, STAT2, TACC3, TAPl, TAX1BP3, THEMIS2, THTPA, TIMM8B, TNFAIP8L2, TNFSF8, TOP2A, TP53I3, TPX2, TREX1, TRIB3, TRIM22, TTC39C, TXNIP, UBA7, UBE2L6, USP41, VCL, VNN2, WIZ, WSB1, WWC1, ZBTB38, ZFP91, ZMYM2, ZNF385B, ZNF581 and ZNF644.
• the biomarker is selected from a group consisting of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ATP2B4, BMF, BST2, C10orf76, C19orf66, CD36, CLN3, CNN3, COROIB, CPNE2, CRBN, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHX58, DLG2, DTX3L, EIF2AK2,EPB41L1, ETV6, EXTL2, F13A1, FAM65B, FCGR2B, FES, FMNL3, GBPl, GMFG, GMPR, HIP1, HLA-B, HLA-DMA, HPSE, ID3, IFI35, IFIHI, IFITI, IFIT3, IFIT5, IFITM2, IL4I1, IRF7, IRF9, ISG15, ISG20, ITGB7, JAK3, LAP3, LGALS1, LGALS
• the biomarker is selected from a group consisting of ARHGAP19, ASNS, ASPM, B4GALT3, BANK1,
• the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN. In another specific embodiment of the various methods provided herein, the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198.
• the level of only one biomarker is determined. In other embodiments of the various methods provided herein, the levels of two, three, four, five or more biomarkers are determined. [00142] In some embodiments of the various methods provided herein, two or more biomarkers identified in Table 1 and/or Table 2 are measured and compared with the reference sample. In some embodiments, the two or more biomarkers are identified in Table 1, and the levels of the biomarkers increase as compared to the levels of the biomarkers in the reference. In other embodiments of the various methods provided herein, the two or more biomarkers are identified in Table 2, and the levels of the biomarkers decrease as compared to the levels of the biomarkers in the reference.
• one or more biomarkers are identified in Table 1
• one or more biomarkers are identified in Table 2, and the levels of some biomarkers increase as compared to the reference and the level of some biomarkers decrease as compared to the reference.
• the reference is prepared by using a control sample obtained from the subject prior to administration of the treatment compound to the subject; and wherein the control sample is from the same source as the sample.
• the reference is prepared by using a control sample obtained from a healthy subject not having the solid tumor; and wherein the control sample is from the same source as the sample.
• the levels of one or more of the biomarkers are measured by determining the mRNA levels of the biomarkers.
• the mRNA levels of the biomarkers are determined by reverse transcriptase PCR (RT-PCR).
• the mRNA levels of the biomarkers are determined by quantitative RT-PCR (qRT-PCR).
• the levels of one or more of the biomarkers are measured by determining the cDNA levels of the biomarkers.
• the cDNA levels of the biomarkers are determined by PCR.
• the levels of one or more of the biomarkers are measured by determining the protein levels of the biomarkers.
• the method provided herein further comprises contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the biomarker protein, and wherein the second antibody immunospecifically binds to a different epitope on the biomarker protein than the first antibody; (ii) detecting the presence of second antibody bound to the biomarker protein; and (iii) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (ii) detecting the presence of second antibody bound to the first antibody; and (iii) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.
• the biomarker is ZFP91.
• the method provided herein comprises selecting a group of subjects having a solid tumor, e.g., HCC or GBM, based on the level of ZFP91, or the levels of ZFP91 expression within the solid tumor, e.g., HCC or GBM, for the purposes of predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing by a compound.
• ZFP91 protein degrades in response to treatment with various compounds.
• a reduced level of ZFP91 can be used to identify subjects who are likely to be responsive to treatment with various compounds and/or to predict if further treatment with compounds will receive responsiveness from the subject.
• a method of identifying a patient who is likely to be responsive to a treatment of a solid tumor, e.g., HCC or GBM, with a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of treating a solid tumor comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the level of ZFP91 in the sample is less than 90% of the level of ZFP91 of a reference. In some embodiments, the level of ZFP91 in the sample is less than 80% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 70% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 60% of the level of ZFP91 of a reference. In other
• the level of ZFP91 in the sample is less than 50% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 40% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 30% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 20% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 10% of the level of ZFP91 of a reference.
• the protein level of ZFP91 is measured.
• the method provided herein comprises contacting proteins within the sample with a first antibody that immunospecifically binds to ZFP91 protein.
• the method provided herein further includes (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to ZFP91, and wherein the second antibody immunospecifically binds to a different epitope on ZFP91 protein than the first antibody; (ii) detecting the presence of second antibody bound to the proteins; and (iii) determining the amount of ZFP91 protein based on the amount of detectable label in the second antibody.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (ii) detecting the presence of second antibody bound to the proteins; and (iii) determining the amount of ZFP91 protein based on the amount of detectable label in the second antibody.
• the mR A level of ZFP91 is measured.
• the method provided herein comprises extracting mRNA from the sample.
• the method further comprises determining mRNA level of ZFP91 using PCR.
• the PCR is a RT-PCR.
• the method provided herein further comprises generating cDNA from the mRNA. In some embodiments, the method provided herein further comprises performing a PCR to quantify the cDNA representing ZFP91.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the solid tumor is HCC.
• the solid tumor is GBM.
• the treatment compound is Compound A, and the solid tumor is HCC.
• the treatment compound is Compound B, and the solid tumor is HCC.
• the treatment compound is lenadlidomide, and the solid tumor is HCC.
• the treatment compound is Compound A, and the solid tumor is GBM.
• the treatment compound is Compound B, and the solid tumor is GBM.
• the treatment compound is lenadlidomide, and the solid tumor is GBM.
• the biomarker is CRBN.
• the method provided herein comprises selecting a group of subjects having a solid tumor, e.g., HCC or GBM, based on the level of CRBN, or the levels of CRBN expression within the solid tumor, e.g., HCC or GBM, for the purposes of predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing by a compound.
• CRBN protein level increases in response to treatment with various compounds in HCC or GBM cell lines.
• an increased level of CRBN can be used to identify subjects who are likely to be responsive to treatment with various compounds and/or to predict if further treatment with compounds will receive responsiveness from the subjects.
• a method of identifying a patient who is likely to be responsive to a treatment of a solid tumor with a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of treating a solid tumor comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the level of CRBN in the sample is 10% more than the level of CRBN of a reference. In some embodiments, the level of ZFP91 in the sample is 20% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 30% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 40% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 50% more than the level of CRBN of a reference. In other
• the level of CRBN in the sample is 60% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 70% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 80% of the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 90% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold of the CRBN level of a reference.
• the protein level of CRBN is measured.
• the method provided herein comprises contacting proteins within the sample with a first antibody that immunospecifically binds to CRBN protein.
• the method provided herein further includes (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to CRBN, and wherein the second antibody immunospecifically binds to a different epitope on CRBN protein than the first antibody; (ii) detecting the presence of second antibody bound to the proteins; and (iii) determining the amount of CRBN protein based on the amount of detectable label in the second antibody.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (ii) detecting the presence of second antibody bound to the proteins; and (iii) determining the amount of CRBN protein based on the amount of detectable label in the second antibody.
• the mRNA level of CRBN is measured.
• the method provided herein comprises extracting mRNA from the sample.
• the method further comprises determining mRNA level of CRBN using PCR.
• the PCR is a RT-PCR.
• the method provided herein further comprises generating cDNA from the mR A.
• the method provided herein further comprises performing a PCR to quantify the cDNA representing CRBN.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the solid tumor is HCC.
• the solid tumor is GBM.
• the treatment compound is Compound A, and the solid tumor is HCC.
• the treatment compound is Compound B, and the solid tumor is HCC.
• the treatment compound is lenadlidomide, and the solid tumor is HCC.
• the treatment compound is Compound A, and the solid tumor is GBM.
• the treatment compound is Compound B, and the solid tumor is GBM.
• the treatment compound is lenadlidomide, and the solid tumor is GBM.
• the biomarkers are ZFP91 and CRBN.
• the method provided herein comprises selecting a group of subjects having a solid tumor, e.g., HCC or GBM, based on the levels of ZFP91 and CRBN, or the levels of ZFP91 and CRBN expression within the solid tumor, e.g., HCC or GBM, for the purposes of predicting clinical response, monitoring clinical response, or monitoring patient compliance to dosing by a compound.
• an increased level of CRBN and a decreased level of ZFP91 can be used to identify subjects who are likely to be responsive to treatment with various compounds and/or to predict if further treatment with compounds will receive responsiveness from the subjects.
• a method of identifying a subject who is likely to be responsive to a treatment of a solid tumor, e.g., HCC or GBM, with a treatment compound comprising:
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• the level of ZFP91 in the sample is less than 90% of the level of ZFP91 of a reference. In some embodiments, the level of ZFP91 in the sample is less than 80% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 70% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 60% of the level of ZFP91 of a reference. In other
• the level of ZFP91 in the sample is less than 50% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 40% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 30% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 20% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 10% of the level of ZFP91 of a reference.
• the level of CRBN in the sample is 10% more than the level of CRBN of a reference. In some embodiments, the level of ZFP91 in the sample is 20% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 30% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 40% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 50% more than the level of CRBN of a reference. In other
• the level of CRBN in the sample is 60% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 70% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 80% of the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 90% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold of the CRBN level of a reference.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the solid tumor is HCC.
• the solid tumor is GBM.
• the treatment compound is Compound A, and the solid tumor is HCC.
• the treatment compound is Compound B, and the solid tumor is HCC.
• the treatment compound is lenadlidomide, and the solid tumor is HCC.
• the treatment compound is Compound A, and the solid tumor is GBM.
• the treatment compound is Compound B, and the solid tumor is GBM.
• the treatment compound is lenadlidomide, and the solid tumor is GBM.
• the treatment compound is thalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is lenalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is pomalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is
• the treatment compound is Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by thalidomide, lenalidomide, pomalidomide, Compound A or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a solid tumor e.g., HCC or GBM
• the biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by thalidomide.
• the biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by lenalidomide.
• the biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by pomalidomide.
• the biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by Compound A. In yet other embodiments, the biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by Compound B.
• a method of identifying a subject who is likely to be responsive to a treatment of a solid tumor, e.g., HCC or GBM, with Compound A comprising:
• biomarker determining the level of a biomarker in the sample from the subject, wherein the biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM. [00176] In some embodiments, provided herein is a method of treating a solid tumor, e.g., HCC or GBM, comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. In a specific embodiment of the various methods provided herein, the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198. In some embodiments, the solid tumor is HCC. In some embodiments, the solid tumor is GBM.
• the biomarker is ZFP91, and the solid tumor is HCC.
• the biomarker is CRBN, and the solid tumor is HCC.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is HCC.
• the biomarker is Nestin, and the solid tumor is HCC.
• the biomarker is KAT1/CCBL1, and the solid tumor is HCC.
• the biomarker is WIBG, and the solid tumor is HCC.
• the biomarker is MVP, and the solid tumor is HCC.
• the biomarker is PARP4, and the solid tumor is HCC.
• the biomarker is ZNF198, and the solid tumor is HCC.
• the biomarker is ZFP91, and the solid tumor is GBM.
• the biomarker is CRBN, and the solid tumor is GBM.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is GBM.
• the biomarker is Nestin, and the solid tumor is GBM.
• the biomarker is KAT1/CCBL1, and the solid tumor is GBM.
• the biomarker is WIBG, and the solid tumor is GBM.
• the biomarker is MVP, and the solid tumor is GBM.
• the biomarker is PARP4, and the solid tumor is GBM.
• the biomarker is ZNF198, and the solid tumor is GBM.
• a method of identifying a subject who is likely to be responsive to a treatment of a solid tumor, e.g., HCC or GBM, with Compound B comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. In a specific embodiment of the various methods provided herein, the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198. In some embodiments, the solid tumor is HCC. In some embodiments, the solid tumor is GBM.
• the biomarker is ZFP91, and the solid tumor is HCC.
• the biomarker is CRBN, and the solid tumor is HCC.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is HCC.
• the biomarker is Nestin, and the solid tumor is HCC.
• the biomarker is KAT1/CCBL1, and the solid tumor is HCC.
• the biomarker is WIBG, and the solid tumor is HCC.
• the biomarker is MVP, and the solid tumor is HCC.
• the biomarker is PARP4, and the solid tumor is HCC.
• the biomarker is ZNF198, and the solid tumor is HCC.
• the biomarker is ZFP91, and the solid tumor is GBM.
• the biomarker is CRBN, and the solid tumor is GBM.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is GBM.
• the biomarker is Nestin, and the solid tumor is GBM.
• the biomarker is KAT1/CCBL1, and the solid tumor is GBM.
• the biomarker is WIBG, and the solid tumor is GBM.
• the biomarker is MVP, and the solid tumor is GBM.
• the biomarker is PARP4, and the solid tumor is GBM.
• the biomarker is ZNF198, and the solid tumor is GBM.
• a method of identifying a subject who is likely to be responsive to a treatment of a solid tumor, e.g., HCC or GBM, with lenalidomide comprising:
• biomarker determining the level of a biomarker in the sample from the subject, wherein the biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG.
• the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is ZFP91.
• the biomarker is CRBN.
• the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198. In some embodiments, the solid tumor is HCC. In some embodiments, the solid tumor is GBM.
• the biomarker is ZFP91, and the solid tumor is HCC.
• the biomarker is CRBN, and the solid tumor is HCC.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is HCC.
• the biomarker is Nestin, and the solid tumor is HCC.
• the biomarker is KATl/CCBLl, and the solid tumor is HCC.
• the biomarker is WIBG, and the solid tumor is HCC.
• the biomarker is MVP, and the solid tumor is HCC.
• the biomarker is PARP4, and the solid tumor is HCC.
• the biomarker is ZNF198, and the solid tumor is HCC.
• the biomarker is ZFP91, and the solid tumor is GBM.
• the biomarker is CRBN, and the solid tumor is GBM.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is GBM.
• the biomarker is Nestin, and the solid tumor is GBM.
• the biomarker is KAT1/CCBL1 , and the solid tumor is GBM.
• the biomarker is WIBG, and the solid tumor is GBM.
• the biomarker is MVP, and the solid tumor is GBM.
• the biomarker is PARP4, and the solid tumor is GBM.
• the biomarker is ZNF198, and the solid tumor is GBM.
• the solid tumors are sarcomas, carcinomas (epithelial tumors), melanomas, and glioblastomas.
• Exemplary solid tumors include, but not limited to, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g. , meningioma; glioma, e.g.
• astrocytoma oligodendroglioma, glioblastoma (GBM); medulloblastoma
• cervical cancer e.g., cervical adenocarcinoma
• colorectal cancer e.g., colon cancer, rectal cancer, colorectal adenocarcinoma
• gastric cancer e.g., stomach adenocarcinoma
• head and neck cancer e.g., head and neck squamous cell carcinoma
• oral cancer e.g., oral squamous cell carcinoma (OSCC)
• kidney cancer e.g., nephroblastoma a.k.a.
• liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
• lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
• neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2
• NF neurofibromatosis
• neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), pancreatic cancer (e.g., pancreatic
• the solid tumor is a liver cancer.
• the solid tumor is HCC.
• the solid tumor is a brain cancer.
• the solid tumor is GBM.
• a method of identifying a subject having HCC who is likely to be responsive to a treatment compound comprising:
• biomarker determining the level of a biomarker in the sample from the subject, wherein the biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• a method of treating HCC comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, and WIBG.
• the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is ZFP91.
• the biomarker is CRBN.
• the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the biomarker is ZFP91, and the treatment compound is Compound A.
• the biomarker is CRBN, and the treatment compound is Compound A.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is Compound A.
• the biomarker is Nestin, and the treatment compound is Compound A.
• the biomarker is KATl/CCBLl, and the treatment compound is Compound A.
• the biomarker is WIBG, and the treatment compound is Compound A.
• the biomarker is MVP, and the treatment compound is Compound A.
• the biomarker is PARP4, and the treatment compound is Compound A.
• the biomarker is ZNF198, and the treatment compound is Compound A.
• the biomarker is ZFP91, and the treatment compound is Compound B.
• the biomarker is CRBN, and the treatment compound is Compound B.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is Compound B.
• the biomarker is Nestin, and the treatment compound is Compound B.
• the biomarker is KATl/CCBLl, and the treatment compound is Compound B.
• the biomarker is WIBG, and the treatment compound is Compound B.
• the biomarker is MVP, and the treatment compound is Compound B.
• the biomarker is PARP4, and the treatment compound is Compound B.
• the biomarker is ZNF198, and the treatment compound is
• the biomarker is ZFP91, and the treatment compound is lenalidomide.
• the biomarker is CRBN, and the treatment compound is lenalidomide.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is lenalidomide.
• the biomarker is Nestin, and the treatment compound is lenalidomide.
• the biomarker is KATl/CCBLl, and the treatment compound is lenalidomide.
• the biomarker is WIBG, and the treatment compound is lenalidomide.
• the biomarker is MVP, and the treatment compound is lenalidomide.
• the biomarker is PARP4, and the treatment compound is lenalidomide.
• the biomarker is ZNF198, and the treatment compound is
• a method of identifying a subject having GBM who is likely to be responsive to a treatment compound comprising: (a) administering the treatment compound to a subject having GBM;
• biomarker determining the level of a biomarker in the sample from the subject, wherein the biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• a method of treating GBM comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. In a specific embodiment of the various methods provided herein, the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the biomarker is ZFP91, and the treatment compound is Compound A.
• the biomarker is CRBN, and the treatment compound is Compound A.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is Compound A.
• the biomarker is Nestin, and the treatment compound is Compound A.
• the biomarker is KATl/CCBLl, and the treatment compound is Compound A.
• the biomarker is WIBG, and the treatment compound is Compound A.
• the biomarker is MVP, and the treatment compound is Compound A.
• the biomarker is PARP4, and the treatment compound is Compound A.
• the biomarker is ZNF198, and the treatment compound is Compound A.
• the biomarker is ZFP91, and the treatment compound is Compound B.
• the biomarker is CRBN, and the treatment compound is Compound B.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is Compound B.
• the biomarker is Nestin, and the treatment compound is Compound B.
• the biomarker is KATl/CCBLl, and the treatment compound is Compound B.
• the biomarker is WIBG, and the treatment compound is Compound B.
• the biomarker is MVP, and the treatment compound is Compound B.
• the biomarker is PARP4, and the treatment compound is Compound B.
• the biomarker is ZNF198, and the treatment compound is
• the biomarker is ZFP91, and the treatment compound is lenalidomide.
• the biomarker is CRBN, and the treatment compound is lenalidomide.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is lenalidomide.
• the biomarker is Nestin, and the treatment compound is lenalidomide.
• the biomarker is KATl/CCBLl, and the treatment compound is lenalidomide.
• the biomarker is WIBG, and the treatment compound is lenalidomide.
• the biomarker is MVP, and the treatment compound is lenalidomide.
• the biomarker is PARP4, and the treatment compound is lenalidomide.
• the biomarker is ZNF198, and the treatment compound is
• a treatment compound is administered to a patient likely to be responsive to the treatment compound.
• the compound is administered to a patient as a dose of from about 0.1 mg per day to about 100 mg per day.
• the treatment compound is administered a patient as a dose of between about 0.5 mg per day to about 100 mg per day.
• the treatment compound is administered a patient as a dose of between about 0.5 mg per day to about 20 mg per day. In other embodiments, the treatment compound is administered a patient as a dose of between about 5 mg per day to about 25 mg per day. In some embodiments, the treatment compound is administered a patient as a dose of between about 0.5 mg per day to about 10 mg per day. In certain embodiments, the treatment compound is administered a patient as a dose of between about 0.5 mg per day to about 100 mg per day.
• the treatment compound is administered at a dose of about O. lmg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg per day.
• the treatment compound is administered once daily. In some embodiments, the treatment compound is administered twice daily. In certain embodiments, the treatment compound is cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Accordingly, in some embodiments, about 0.5 mg per day to about 100 mg per day of the treatment compound is administered on days 1-12 of a repeated 28 day cycle. In a specific embodiment, 25 mg of the treatment compound is administered once a day on days 1-12 of a repeated 28 day cycle.
• a treatment compound can be administered by any route of administration known in the art, such as oral, intravenous, subcutaneous, or intramucosal administration.
• lenalidomide or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• Compound A or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• thalidomide or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• pomalidomide or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• Compound B or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• the oral dosage form can be a tablet or a capsule. In some embodiments, the dosage form is a tablet. In some other embodiments, the dosage for is a capsule.
• biomarkers Based, in part, on the finding that detectable increase or decrease in certain biomarkers are observed in subjects with a solid tumor, e.g., HCC or GBM, who are responsive to a given treatment ⁇ e.g., a treatment by a treatment compound, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof), the levels of these biomarkers may be used for predicting the responsiveness of the subjects to the treatment.
• a treatment compound e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor e.g., HCC or GBM, to a treatment compound.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM. [00213] in yet another aspect, provided herein is a method of monitoring the efficacy of a treatment of a solid tumor, e.g., HCC or GBM, in a subject with a treatment compound, comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor comprising: (a) administering the treatment compound to a subject having a solid tumor;
• biomarker is selected from the group consisting of biomarkers identified in Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is selected from a group consisting of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6,
• SAMD9L SAMHD1, SEC14L1, SERPINH1, SGOLl, SGOL2, SLC03A1, SLC04A1,
• SLFNl l SLFN13, SLFN5, SPl lO, SP140, SPN, SPR, STAPl, STATl, STAT2, TACC3, TAPl, TAX1BP3, THEMIS2, THTPA, TIMM8B, TNFAIP8L2, TNFSF8, TOP2A, TP53I3, TPX2, TREX1, TRIB3, TRIM22, TTC39C, TXNIP, UBA7, UBE2L6, USP41, VCL, VNN2, WIZ, WSB1, WWC1, ZBTB38, ZFP91, ZMYM2, ZNF385B, ZNF581 and ZNF644.
• the biomarker is selected from a group consisting of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ATP2B4, BMF, BST2, C10orf76, C19orf66, CD36, CLN3, CNN3, COROIB, CPNE2, CRBN, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHX58, DLG2, DTX3L, EIF2AK2,EPB41L1, ETV6, EXTL2, F13A1, FAM65B, FCGR2B, FES, FMNL3, GBP1, GMFG, GMPR, HIP1, HLA-B, HLA-DMA, HPSE, ID3, IFI35, IFIHI, IFITI, IFIT3, IFIT5, IFITM2, IL4I1, IRF7, IRF9, ISG15, ISG20, ITGB7, JAK3, LAP3, LGALS1, LGALS
• the biomarker is selected from a group consisting of ARHGAP19, ASNS, ASPM, B4GALT3, BANK1,
• BCDIN3D BCDIN3D, BLZF1, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CDC7, CDC A3, CENPF, CSNK1A1DHPS, DLGAP5, DOK3, ECT2, EFCAB4B, EHMT1, EHMT2, EPCAM, ESRP1, FAM195A, FBRSL1, FHOD1, FIGNL1, GPT2, GRAMD1A, GRAMD1B, GRPEL2, HJURP, HMCES, HMMR, HOXC4, ICAM2, IKZF1, IKZF3, IRS2, KIF18B, KIF22, KIF2C, LIPG, LPXN, MINA, MIS18BP1, NEILl, NFKBID, NPIPB5, OMAl, ORC6, PARVB, PBK, PDE6D, PKMYT1, PLK1, PODXL, PODXL2, POLE2, PRDM15, PRNP, PTAFR, PTTG1, PYROXD
• the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN. In another specific embodiment of the various methods provided herein, the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KAT1/CCBL1. In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198.
• the level of only one biomarker is determined. In other embodiments of the various methods provided herein, the levels of two, three, four, five or more biomarkers are determined.
• two or more biomarkers identified in Table 1 and Table 2 are measured and compared with the reference sample.
• the two or more biomarkers are identified in Table 1, and the levels of the biomarkers increase as compared to the levels of the biomarkers in the reference.
• the two or more biomarkers are identified in Table 2, and the levels of the biomarkers decrease as compared to the levels of the biomarkers in the reference.
• one or more biomarkers are identified in Table 1
• one or more biomarkers are identified in Table 2, and the levels of some biomarkers increase as compared to the reference and the level of some biomarkers decrease as compared to the reference.
• the reference is prepared by using a control sample obtained from the subject prior to administration of the treatment compound to the subject; and wherein the control sample is from the same source as the sample.
• the reference is prepared by using a control sample obtained from a healthy subject not having the solid tumor; and wherein the control sample is from the same source as the sample.
• the levels of one or more of the biomarkers are measured by determining the mRNA levels of the biomarkers.
• the mRNA levels of the biomarkers are determined by reverse transcriptase PCR (RT-PCR).
• the mRNA levels of the biomarkers are determined by quantitative RT-PCR (qRT-PCR).
• the levels of one or more of the biomarkers are measured by determining the cDNA levels of the biomarkers.
• the cDNA levels of the biomarkers are determined by PCR.
• the levels of one or more of the biomarkers are measured by determining the protein levels of the biomarkers.
• the method provided herein further comprises contacting proteins within the sample with a first antibody that immunospecifically binds to the biomarker protein.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the biomarker protein, and wherein the second antibody immunospecifically binds to a different epitope on the biomarker protein than the first antibody; (ii) detecting the presence of second antibody bound to the biomarker protein; and (iii) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (ii) detecting the presence of second antibody bound to the first antibody; and (iii) determining the amount of the biomarker protein based on the amount of detectable label in the second antibody.
• the biomarker is ZFP91.
• responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor e.g., HCC or GBM, in a subject with a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the level of ZFP91 in the sample is less than 90% of the level of ZFP91 of a reference. In some embodiments, the level of ZFP91 in the sample is less than 80% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 70% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 60% of the level of ZFP91 of a reference. In other
• the level of ZFP91 in the sample is less than 50% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 40% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 30% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 20% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 10% of the level of ZFP91 of a reference.
• the protein level of ZFP91 is measured.
• the method provided herein comprises contacting proteins within the sample with a first antibody that immunospecifically binds to ZFP91 protein.
• the method provided herein further includes (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to ZFP91, and wherein the second antibody immunospecifically binds to a different epitope on ZFP91 protein than the first antibody; (ii) detecting the presence of second antibody bound to the proteins; and (iii) determining the amount of ZFP91 protein based on the amount of detectable label in the second antibody.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (ii) detecting the presence of second antibody bound to the proteins; and (iii) determining the amount of ZFP91 protein based on the amount of detectable label in the second antibody.
• the mR A level of ZFP91 is measured.
• the method provided herein comprises extracting mRNA from the sample.
• the method further comprises determining mRNA level of ZFP91 using PCR.
• the PCR is a RT-PCR.
• the method provided herein further comprises generating cDNA from the mRNA. In some embodiments, the method provided herein further comprises performing a PCR to quantify the cDNA representing ZFP91.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the solid tumor is HCC.
• the solid tumor is GBM.
• the treatment compound is Compound A, and the solid tumor is HCC.
• the treatment compound is Compound B, and the solid tumor is HCC. In some embodiments, the treatment compound is lenadlidomide, and the solid tumor is HCC. In some embodiments, the treatment compound is Compound A, and the solid tumor is GBM. In some embodiments, the treatment compound is Compound B, and the solid tumor is GBM. In some embodiments, the treatment compound is lenadlidomide, and the solid tumor is GBM.
• the biomarker is CRBN.
• a method of predicting the biomarker is CRBN.
• responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor e.g., HCC or GBM, in a subject with a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the level of CRBN in the sample is 10% more than the level of CRBN of a reference. In some embodiments, the level of ZFP91 in the sample is 20% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 30% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 40% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 50% more than the level of CRBN of a reference. In other
• the level of CRBN in the sample is 60% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 70% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 80% of the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 90% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold of the CRBN level of a reference.
• the protein level of CRBN is measured.
• the method provided herein comprises contacting proteins within the sample with a first antibody that immunospecifically binds to CRBN protein.
• the method provided herein further includes (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to CRBN, and wherein the second antibody immunospecifically binds to a different epitope on CRBN protein than the first antibody; (ii) detecting the presence of second antibody bound to the proteins; and (iii) determining the amount of CRBN protein based on the amount of detectable label in the second antibody.
• the method provided herein further comprises (i) contacting the proteins bound to the first antibody with a second antibody with a detectable label, wherein the second antibody immunospecifically binds to the first antibody; (ii) detecting the presence of second antibody bound to the proteins; and (iii) determining the amount of CRBN protein based on the amount of detectable label in the second antibody.
• the mRNA level of CRBN is measured.
• the method provided herein comprises extracting mRNA from the sample.
• the method further comprises determining mRNA level of CRBN using PCR.
• the PCR is a RT-PCR.
• the method provided herein further comprises generating cDNA from the mR A.
• the method provided herein further comprises performing a PCR to quantify the cDNA representing CRBN.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the solid tumor is HCC.
• the solid tumor is GBM.
• the treatment compound is Compound A, and the solid tumor is HCC.
• the treatment compound is Compound B, and the solid tumor is HCC.
• the treatment compound is lenadlidomide, and the solid tumor is HCC.
• the treatment compound is Compound A, and the solid tumor is GBM.
• the treatment compound is Compound B, and the solid tumor is GBM.
• the treatment compound is lenadlidomide, and the solid tumor is GBM.
• the biomarkers are ZFP91 and CRBN.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM. [00245] In some embodiments, provided herein is a method of monitoring the efficacy of a treatment of a solid tumor, e.g., HCC or GBM, in a subject with a treatment compound, comprising:
• the level of ZFP91 in the sample is less than 90% of the level of ZFP91 of a reference. In some embodiments, the level of ZFP91 in the sample is less than 80% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 70% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 60% of the level of ZFP91 of a reference. In other
• the level of ZFP91 in the sample is less than 50% of the level of ZFP91 of a reference. In other embodiments, the level of ZFP91 in the sample is less than 40% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 30% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 20% of the level of ZFP91 of a reference. In yet other embodiments, the level of ZFP91 in the sample is less than 10% of the level of ZFP91 of a reference.
• the level of CRBN in the sample is 10% more than the level of CRBN of a reference. In some embodiments, the level of ZFP91 in the sample is 20% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 30% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 40% more than the level of CRBN of a reference. In other embodiments, the level of CRBN in the sample is 50% more than the level of CRBN of a reference. In other
• the level of CRBN in the sample is 60% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 70% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 80% of the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 90% more than the level of CRBN of a reference. In yet other embodiments, the level of CRBN in the sample is 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold of the CRBN level of a reference.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the solid tumor is HCC.
• the solid tumor is GBM.
• the treatment compound is Compound A, and the solid tumor is HCC.
• the treatment compound is Compound B, and the solid tumor is HCC. In some embodiments, the treatment compound is lenadlidomide, and the solid tumor is HCC. In some embodiments, the treatment compound is Compound A, and the solid tumor is GBM. In some embodiments, the treatment compound is Compound B, and the solid tumor is GBM. In some embodiments, the treatment compound is lenadlidomide, and the solid tumor is GBM.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is thalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is lenalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is pomalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is
• the treatment compound is Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the biomarkers are used to predict and/or monitor efficacy of a treatment with thalidomide, lenalidomide, pomalidomide, Compound A or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the biomarkers are used to predict and/or monitor efficacy of a treatment with thalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the biomarkers are used to predict and/or monitor efficacy of a treatment with lenalidomide, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the biomarkers are used to predict and/or monitor efficacy of a treatment with pomalidomide, or a stereoisomer thereof, or a
• the biomarkers are used to predict and/or monitor efficacy of a treatment with Compound A, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the biomarkers are used to predict and/or monitor efficacy of a treatment with Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to Compound A comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor, e.g., HCC or GBM, in a subject with Compound A comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. In a specific embodiment of the various methods provided herein, the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198. In some embodiments, the solid tumor is HCC. In some embodiments, the solid tumor is GBM.
• the biomarker is ZFP91, and the solid tumor is HCC.
• the biomarker is CRBN, and the solid tumor is HCC.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is HCC.
• the biomarker is Nestin, and the solid tumor is HCC.
• the biomarker is KAT1/CCBL1, and the solid tumor is HCC.
• the biomarker is WIBG, and the solid tumor is HCC.
• the biomarker is MVP, and the solid tumor is HCC.
• the biomarker is PARP4, and the solid tumor is HCC.
• the biomarker is ZNF198, and the solid tumor is HCC.
• the biomarker is ZFP91, and the solid tumor is GBM.
• the biomarker is CRBN, and the solid tumor is GBM.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is GBM.
• the biomarker is Nestin, and the solid tumor is GBM.
• the biomarker is KAT1/CCBL1, and the solid tumor is GBM.
• the biomarker is WIBG, and the solid tumor is GBM.
• the biomarker is MVP, and the solid tumor is GBM.
• the biomarker is PARP4, and the solid tumor is GBM.
• the biomarker is ZNF198, and the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to Compound B comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor e.g., HCC or GBM, in a subject with Compound B, comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. In a specific embodiment of the various methods provided herein, the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198. In some embodiments, the solid tumor is HCC. In some embodiments, the solid tumor is GBM.
• the biomarker is ZFP91, and the solid tumor is HCC.
• the biomarker is CRBN, and the solid tumor is HCC.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is HCC.
• the biomarker is Nestin, and the solid tumor is HCC.
• the biomarker is KAT1/CCBL1, and the solid tumor is HCC.
• the biomarker is WIBG, and the solid tumor is HCC.
• the biomarker is MVP, and the solid tumor is HCC.
• the biomarker is PARP4, and the solid tumor is HCC.
• the biomarker is ZNF198, and the solid tumor is HCC.
• the biomarker is ZFP91, and the solid tumor is GBM.
• the biomarker is CRBN, and the solid tumor is GBM.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is GBM.
• the biomarker is Nestin, and the solid tumor is GBM.
• the biomarker is KAT1/CCBL1, and the solid tumor is GBM.
• the biomarker is WIBG, and the solid tumor is GBM.
• the biomarker is MVP, and the solid tumor is GBM.
• the biomarker is PARP4, and the solid tumor is GBM.
• the biomarker is ZNF198, and the solid tumor is GBM.
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a subject with lenalidomide comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. In a specific embodiment of the various methods provided herein, the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198. In some embodiments, the solid tumor is HCC. In some embodiments, the solid tumor is GBM.
• the biomarker is ZFP91, and the solid tumor is HCC.
• the biomarker is CRBN, and the solid tumor is HCC.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is HCC.
• the biomarker is Nestin, and the solid tumor is HCC.
• the biomarker is KATl/CCBLl, and the solid tumor is HCC.
• the biomarker is WIBG, and the solid tumor is HCC.
• the biomarker is MVP, and the solid tumor is HCC.
• the biomarker is PARP4, and the solid tumor is HCC.
• the biomarker is ZNF198, and the solid tumor is HCC.
• the biomarker is ZFP91, and the solid tumor is GBM.
• the biomarker is CRBN, and the solid tumor is GBM.
• the biomarkers are both ZFP91 and CRBN, and the solid tumor is GBM.
• the biomarker is Nestin, and the solid tumor is GBM.
• the biomarker is KATl/CCBLl, and the solid tumor is GBM.
• the biomarker is WIBG, and the solid tumor is GBM.
• the biomarker is MVP, and the solid tumor is GBM.
• the biomarker is PARP4, and the solid tumor is GBM.
• the biomarker is ZNF198, and the solid tumor is GBM.
• the level of the biomarker is measured in an in vitro assay to predict the responsiveness of a subject to a treatment of a solid tumor ⁇ e.g., a treatment by a treatment compound provided herein), comprising obtaining a sample of cells from the subject, culturing the cells in the presence or absence of a treatment compound, and testing the cells for the levels of the biomarkers, wherein an increased or a decreased level of the biomarker in the presence of the treatment compound indicates the likelihood of responsiveness of the subject to the treatment compound.
• the solid tumors are sarcomas, carcinomas (epithelial tumors), melanomas, and glioblastomas.
• Exemplary solid tumors include, but not limited to, biliary cancer ⁇ e.g., cholangiocarcinoma), bladder cancer, breast cancer ⁇ e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer ⁇ e.g. , meningioma; glioma, e.g.
• astrocytoma oligodendroglioma, glioblastoma (GBM); medulloblastoma
• cervical cancer ⁇ e.g., cervical adenocarcinoma
• colorectal cancer ⁇ e.g., colon cancer
• rectal cancer colorectal adenocarcinoma
• gastric cancer ⁇ e.g., stomach adenocarcinoma
• gastrointestinal stromal tumor GIST
• head and neck cancer ⁇ e.g., head and neck squamous cell carcinoma
• oral cancer ⁇ e.g., oral squamous cell carcinoma (OSCC)
• kidney cancer ⁇ e.g., nephroblastoma a.k.a.
• liver cancer ⁇ e.g., hepatocellular cancer (HCC), malignant hepatoma
• lung cancer ⁇ e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung), neuroblastoma, neurofibroma ⁇ e.g., neurofibromatosis (NF) type 1 or type 2,
• neuroendocrine cancer ⁇ e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer ⁇ e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), pancreatic cancer ⁇ e.g., pancreatic
• the solid tumor is a liver cancer.
• the solid tumor is HCC.
• the solid tumor is a brain cancer.
• the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having HCC, to a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• a method of monitoring the efficacy of a treatment of HCC, in a subject with a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1 , WIBG, MVP, PARP4, ZFP91 , and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KAT1/CCBL1 , and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. In a specific embodiment of the various methods provided herein, the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the biomarker is ZFP91, and the treatment compound is Compound A.
• the biomarker is CRBN, and the treatment compound is Compound A.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is Compound A.
• the biomarker is Nestin, and the treatment compound is Compound A.
• the biomarker is KATl/CCBLl, and the treatment compound is Compound A.
• the biomarker is WIBG, and the treatment compound is Compound A.
• the biomarker is MVP, and the treatment compound is Compound A.
• the biomarker is PARP4, and the treatment compound is Compound A.
• the biomarker is ZNF198, and the treatment compound is Compound A.
• the biomarker is ZFP91, and the treatment compound is Compound B.
• the biomarker is CRBN, and the treatment compound is Compound B.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is Compound B.
• the biomarker is Nestin, and the treatment compound is Compound B.
• the biomarker is KATl/CCBLl, and the treatment compound is Compound B.
• the biomarker is WIBG, and the treatment compound is Compound B.
• the biomarker is MVP, and the treatment compound is Compound B.
• the biomarker is PARP4, and the treatment compound is Compound B.
• the biomarker is ZNF198, and the treatment compound is
• the biomarker is ZFP91, and the treatment compound is lenalidomide.
• the biomarker is CRBN, and the treatment compound is lenalidomide.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is lenalidomide.
• the biomarker is Nestin, and the treatment compound is lenalidomide.
• the biomarker is KATl/CCBLl, and the treatment compound is lenalidomide.
• the biomarker is WIBG, and the treatment compound is lenalidomide.
• the biomarker is MVP, and the treatment compound is lenalidomide.
• the biomarker is PARP4, and the treatment compound is lenalidomide.
• the biomarker is ZNF198, and the treatment compound is
• a method of predicting the responsiveness of a subject having or suspected of having GBM, to a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• a method of monitoring the efficacy of a treatment of GBM, in a subject with a treatment compound comprising:
• biomarker is selected from the group consisting of biomarkers identified in Table 1 and Table 2, and combinations thereof;
• the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is selected from a group consisting of Nestin, KATl/CCBLl, and WIBG. In other embodiments, the biomarker is selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198. In a specific embodiment of the various methods provided herein, the biomarker is ZFP91. In another embodiment of the various methods provided herein, the biomarker is CRBN. In yet another embodiment of the various methods provided herein, the biomarkers are both ZFP91 and CRBN.
• the biomarker is Nestin. In another specific embodiment of the various methods provided herein, the biomarker is KATl/CCBLl . In another specific embodiment of the various methods provided herein, the biomarker is WIBG. In another specific embodiment of the various methods provided herein, the biomarker is MVP. In yet another specific embodiment of the various methods provided herein, the biomarker is PARP4. In yet another specific embodiment of the various methods provided herein, the biomarker is ZNF198.
• the treatment compound is thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• the treatment compound is Compound A.
• the treatment compound is Compound B.
• the treatment compound is lenadlidomide.
• the biomarker is ZFP91, and the treatment compound is Compound A.
• the biomarker is CRBN, and the treatment compound is Compound A.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is Compound A.
• the biomarker is Nestin, and the treatment compound is Compound A.
• the biomarker is KATl/CCBLl, and the treatment compound is Compound A.
• the biomarker is WIBG, and the treatment compound is Compound A.
• the biomarker is MVP, and the treatment compound is Compound A.
• the biomarker is PARP4, and the treatment compound is Compound A.
• the biomarker is ZNF198, and the treatment compound is Compound A.
• the biomarker is ZFP91, and the treatment compound is Compound B.
• the biomarker is CRBN, and the treatment compound is Compound B.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is Compound B.
• the biomarker is Nestin, and the treatment compound is Compound B.
• the biomarker is KATl/CCBLl, and the treatment compound is Compound B.
• the biomarker is WIBG, and the treatment compound is Compound B.
• the biomarker is MVP, and the treatment compound is Compound B.
• the biomarker is PARP4, and the treatment compound is Compound B.
• the biomarker is ZNF198, and the treatment compound is
• the biomarker is ZFP91, and the treatment compound is lenalidomide.
• the biomarker is CRBN, and the treatment compound is lenalidomide.
• the biomarkers are both ZFP91 and CRBN, and the treatment compound is lenalidomide.
• the biomarker is Nestin, and the treatment compound is lenalidomide.
• the biomarker is KATl/CCBLl, and the treatment compound is lenalidomide.
• the biomarker is WIBG, and the treatment compound is lenalidomide.
• the biomarker is MVP, and the treatment compound is lenalidomide.
• the biomarker is PARP4, and the treatment compound is lenalidomide.
• the biomarker is ZNF198, and the treatment compound is
• a treatment compound is administered to a patient likely to be responsive to the treatment compound.
• the compound is administered to a patient as a dose of from about 0.1 mg per day to about 100 mg per day.
• the treatment compound is administered a patient as a dose of between about 0.5 mg per day to about 100 mg per day.
• the treatment compound is administered a patient as a dose of between about 0.5 mg per day to about 20 mg per day.
• the treatment compound is administered a patient as a dose of between about 5 mg per day to about 25 mg per day.
• the treatment compound is administered a patient as a dose of between about 0.5 mg per day to about 10 mg per day. In certain embodiments, the treatment compound is administered a patient as a dose of between about 0.5 mg per day to about 100 mg per day.
• the treatment compound is administered at a dose of about O. lmg, 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4.0 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 11 mg, 12 mg, 13 mg, 14 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg per day.
• the treatment compound is administered once daily. In some embodiments, the treatment compound is administered twice daily. In certain embodiments, the treatment compound is cyclically administered to a patient. Cycling therapy involves the administration of an active agent for a period of time, followed by a rest for a period of time, and repeating this sequential administration. Accordingly, in some embodiments, about 0.5 mg per day to about 100 mg per day of the treatment compound is administered on days 1-12 of a repeated 28 day cycle. In a specific embodiment, 25 mg of the treatment compound is administered once a day on days 1-12 of a repeated 28 day cycle.
• a treatment compound can be administered by any route of administration known in the art, such as oral, intravenous, subcutaneous, or intramucosal administration.
• lenalidomide or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• Compound A or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• thalidomide or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• pomalidomide or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• Compound B or a stereoisomer thereof; or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate thereof; or a polymorph thereof is administered to a patient orally.
• the oral dosage form can be a tablet or a capsule. In some embodiments, the dosage form is a tablet. In some other embodiments, the dosage for is a capsule.
• the levels of the mRNA biomarkers may be used for identifying a subject having the solid tumor for the treatment by a treatment compound provided herein.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference level is determined from a non solid tumor- cell-containing sample from the same subject. In certain embodiments, the reference level is determined from a non solid-tumor-cell-containing sample from a group of subjects.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• control sample is a non solid tumor cell containing sample from the same subject. In certain embodiments, the control sample is a non solid tumor cell containing sample from a group of subjects.
• a method of identifying a subject having a solid tumor e.g. , HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor comprising: (a) determining the level of an mR A biomarker in a solid tumor cell-containing sample from the subject; and
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM. [00301] In certain embodiments, provided herein is a method of identifying a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference is prepared by using a control sample obtained from the subject prior to administration of the treatment compound to the subject; and wherein the control sample is from the same source as the sample.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference is prepared by using a control sample obtained from a healthy subject not having a solid tumor, e.g., HCC or GBM; and wherein the control sample is from the same source as the sample.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of identifying a subject having a solid tumor e.g., HCC or GBM, who is likely to be responsive to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the methods provided herein are coupled with a treatment by a treatment compound provided herein, e.g., thalidomide, lenalidomide, pomalidomide,
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference is prepared by using a control sample obtained from the subject prior to administration of the treatment compound to the subject; and wherein the control sample is from the same source as the sample.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g. , HCC or GBM
• a solid tumor e.g. , HCC or GBM
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference is prepared by using a control sample obtained from a healthy subject not having the solid tumor; and wherein the control sample is from the same source as the sample.
• a method of treating a solid tumor e.g., HCC or GBM, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g. , HCC or GBM
• a solid tumor e.g. , HCC or GBM
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a solid tumor e.g., HCC or GBM
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference level is determined simultaneously with the sample. In certain embodiments, the reference level is determined independently from the sample.
• the biomarker is an mRNA of a protein selected from a group consisting of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is an mRNA of a protein selected from a group consisting of Nestin,
• the biomarker is an mRNA of a protein selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is an mRNA of a protein selected from a group consisting of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ARHGAP19, ASNS, ASPM, ATP2B4, B4GALT3, BANK1, BCDIN3D, BLZF1, BMF, BST2, C10orf76, C19orf66, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CD36, CDC7, CDC A3, CENPF, CLN3, CNN3, COROIB, CPNE2, CRBN, CSNK1A1, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHPS, DHX58, DLG2, DLGAP5, DOK3, DTX3L, ECT2, EFCAB4B, EHMTl, EHMT2, EIF2AK2, EPB41L1, EPCAM, ESRPl, ETV6, EX
• SLFNl l SLFN13, SLFN5, SPl lO, SP140, SPN, SPR, STAPl, STATl, STAT2, TACC3, TAPl, TAX1BP3, THEMIS2, THTPA, TIMM8B, TNFAIP8L2, TNFSF8, TOP2A, TP53I3, TPX2, TREXl, TRIB3, TRIM22, TTC39C, TXNIP, UBA7, UBE2L6, USP41, VCL, VNN2, WIZ, WSBl, WWCl, ZBTB38, ZFP91, ZMYM2, ZNF385B, ZNF581 and ZNF644.
• the biomarker is an mRNA of a protein selected from a group consisting of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ATP2B4, BMF, BST2, C10orf76, C19orf66, CD36, CLN3, CNN3, COROIB, CPNE2, CRBN, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHX58, DLG2, DTX3L,
• TNFAIP8L2 TNFSF8, TP53I3, TREXl, TRIM22, TTC39C, TXNIP, UBA7, UBE2L6, USP41, VCL, VNN2 and ZBTB38.
• the biomarker is an mRNA of a protein selected from a group consisting of ARHGAP19, ASNS, ASPM, B4GALT3, BANK1, BCDIN3D, BLZF1, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CDC7, CDC A3, CENPF, CSNK1A1DHPS, DLGAP5, DOK3, ECT2, EFCAB4B, EHMT1, EHMT2, EPCAM, ESRP1, FAM195A, FBRSL1, FHOD1, FIGNL1, GPT2, GRAMD1A, GRAMD1B, GRPEL2, HJURP, HMCES, HMMR, HOXC4, ICAM2, IKZF1, IKZF3, IRS2, KIF18B, KIF22, KIF2C, LIPG, LPXN, MINA, MIS18BP1, NEIL1, NFKBID, NPIPB5, OMA1, ORC6, PARVB,
• the biomarker is an mRNA of ZFP91. In another embodiment, the biomarker is an mRNA of CRBN. In yet another embodiment, the biomarkers are mRNAs of ZFP91 and CRBN. In another specific embodiment of the various methods provided herein, the biomarker is Nestin. In another specific embodiment, the biomarker is an mRNA of KATl/CCBLl . In another specific embodiment, the biomarker is an mRNA of WIBG. In another specific embodiment, the biomarker is an mRNA of MVP. In yet another specific embodiment, the biomarker is an mRNA of PARP4. In yet another specific specific
• the biomarker is an mRNA of ZNF198.
• the mRNA biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a solid tumor e.g., HCC or GBM
• the mRNA biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by thalidomide.
• the mRNA biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by lenalidomide.
• the mRNA biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by pomalidomide.
• the mRNA biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by Compound A. In yet another embodiment, the mRNA biomarkers are used to identify a subject having a solid tumor, e.g., HCC or GBM, who is likely to be responsive to treatment by Compound B.
• the level of the mRNA biomarker is measured in a biological sample obtained from the subject.
• the level of the mRNA biomarker is measured in an in vitro assay to predict the responsiveness of a subject to a treatment of a solid tumor, e.g., HCC or GBM, comprising obtaining a sample of cells from the subject, culturing the cells in the presence or absence of a treatment compound, and testing the cells for the levels of the biomarkers, wherein a decreased level of the biomarker in the presence of the treatment compound indicates the likelihood of responsiveness of the subject to the treatment compound.
• a solid tumor e.g., HCC or GBM
• the level of only one of the mR A biomarkers is monitored. In certain embodiments, the levels of two or more of the mRNA biomarkers are monitored simultaneously.
• the solid tumors are sarcomas, carcinomas (epithelial tumors), melanomas, and glioblastomas.
• Exemplary solid tumors include, but not limited to, biliary cancer (e.g., cholangiocarcinoma), bladder cancer, breast cancer (e.g., adenocarcinoma of the breast, papillary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast), brain cancer (e.g. , meningioma; glioma, e.g.
• astrocytoma oligodendroglioma, glioblastoma (GBM); medulloblastoma
• cervical cancer e.g., cervical adenocarcinoma
• colorectal cancer e.g., colon cancer, rectal cancer, colorectal adenocarcinoma
• gastric cancer e.g., stomach adenocarcinoma
• head and neck cancer e.g., head and neck squamous cell carcinoma
• oral cancer e.g., oral squamous cell carcinoma (OSCC)
• kidney cancer e.g., nephroblastoma a.k.a.
• liver cancer e.g., hepatocellular cancer (HCC), malignant hepatoma
• lung cancer e.g., bronchogenic carcinoma, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung
• neuroblastoma e.g., neurofibromatosis (NF) type 1 or type 2
• NF neurofibromatosis
• neuroendocrine cancer e.g., gastroenteropancreatic neuroendoctrine tumor (GEP-NET), carcinoid tumor), osteosarcoma, ovarian cancer (e.g., cystadenocarcinoma, ovarian embryonal carcinoma, ovarian adenocarcinoma), pancreatic cancer (e.g., pancreatic
• the solid tumor is a liver cancer.
• the solid tumor is HCC.
• the solid tumor is a brain cancer.
• the solid tumor is GBM. 4.3.4 Use of mRNA as biomarkers for predicting the efficacy
• mRNA biomarkers Based, in part, on the finding that detectable increase or decrease in certain mRNA biomarkers are observed in subjects with a solid tumor, e.g., HCC or GBM, who are responsive to a given treatment ⁇ e.g., a treatment by a treatment compound provided herein, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof), the levels of these mRNA biomarkers may be used for predicting the responsiveness of the subjects to the treatment.
• a treatment compound provided herein e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising: (a) obtaining a biological sample from the subject;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor comprising: (a) determining the level of an mR A biomarker in a solid tumor cell-containing sample from the subject;
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM. [00345] In certain embodiments, provided herein is a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference is prepared by using a control sample obtained from the subject prior to administration of the treatment compound to the subject; and wherein the control sample is from the same source as the sample.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference is prepared by using a control sample obtained from a healthy subject not having the solid tumor; and wherein the control sample is from the same source as the sample.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of predicting the responsiveness of a subject having or suspected of having a solid tumor, e.g., HCC or GBM, to a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• control sample is a non-solid tumor cell-containing sample from the same subject. In some embodiments of the various methods provided herein, the control sample is a non-solid tumor cell-containing sample from a group of subjects.
• the level of the mRNA biomarker in a control sample is determined simultaneously with the sample. In other embodiments of the various methods provided herein, the level of the mRNA biomarker in a control sample is determined independently from the sample.
• an increased level of the mRNA biomarker in the sample as compared to the reference level correlates positively with increased responsiveness of the subject to a treatment compound provided herein, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a treatment compound provided herein, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a decreased level of the mRNA biomarker in the sample as compared to the reference level correlates positively with increased responsiveness of the subject to a treatment compound provided herein, e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a treatment compound provided herein e.g., thalidomide, lenalidomide, pomalidomide, Compound A, or Compound B, or a stereoisomer thereof, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, clathrate, or a polymorph thereof.
• a method of monitoring the efficacy of a treatment of a solid tumor e.g., HCC or GBM, in a subject with a treatment compound.
• a solid tumor e.g., HCC or GBM
• a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor, e.g., HCC or GBM, in a subject with a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference is prepared by using a control sample obtained from the subject prior to administration of the treatment compound to the subject; and wherein the control sample is from the same source as the sample.
• a solid tumor e.g., HCC or GBM
• a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM. [00366] In one embodiment, provided herein is a method of monitoring the efficacy of a treatment of a solid tumor, e.g., HCC or GBM, in a subject with a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor e.g., HCC or GBM, in a subject with a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• the reference is prepared by using a control sample obtained from a healthy subject not having a solid tumor; and wherein the control sample is from the same source as the sample.
• a method of monitoring the efficacy of a treatment of a solid tumor e.g., HCC or GBM, in a subject with a treatment compound, comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a method of monitoring the efficacy of a treatment of a solid tumor, e.g., HCC or GBM, in a subject with a treatment compound comprising:
• the solid tumor is HCC. In another embodiment, the solid tumor is GBM.
• a solid tumor e.g., HCC or GBM
• a treatment compound comprising:
• the biomarker is an mRNA of a protein selected from a group consisting of Nestin, KAT1/CCBL1, WIBG, MVP, PARP4, ZFP91, and ZNF198. In some embodiments of the various methods provided herein, the biomarker is an mRNA of a protein selected from a group consisting of Nestin,
• the biomarker is an mRNA of a protein selected from a group consisting of MVP, PARP4, ZFP91, and ZNF198.
• the biomarker is an mRNA of a protein selected from a group consisting of AHNAK, ALOX5, AMPD3, ANXA4, ANXA6, ARHGAP19, ASNS, ASPM, ATP2B4, B4GALT3, BANK1, BCDIN3D, BLZF1, BMF, BST2, C10orf76, C19orf66, CA2, CA8, CAMSAP3, CCDC69, CCNB1, CD36, CDC7, CDC A3, CENPF, CLN3, CNN3, COROIB, CPNE2, CRBN, CSNK1A1, CSRP2, CTNND1, CTSH, DAPK2, DDX58, DHPS, DHX58, DLG2, DLGAP5, DOK3, DTX3L, ECT2, EFCAB4B, EHMTl, EHMT2, EIF2AK2, EPB41L1, EPCAM, ESRPl, ETV6, EX

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