Claims for Patent: 9,725,769

Summary for Patent: 9,725,769

Title:	Methods for predicting drug responsiveness in cancer patients
Abstract:	The present invention features methods, devices, and kits for detecting expression in a patient having cancer or determining responsive of a patient having cancer to a treatment, such as irofulven. The invention further includes methods of treating a patient having cancer by administering, e.g., irofulven.
Inventor(s):	Knudsen; Steen (Scottsdale, AZ)
Assignee:	Oncology Venture ApS (Horsholm, DK)
Application Number:	15/289,026
Patent Claims:	1. A method of testing a tumor sample of a patient having a known cancer type, wherein the patient is resistant to one or more cancer therapies and has an unknown responsiveness to irofulven, comprising: (a) contacting the sample from the patient comprising one or more nucleic acid molecules with a device comprising: i) single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of a plurality of biomarkers of sensitivity selected from the biomarkers of Tables 1 and 3; and ii) single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of a plurality of biomarkers of resistance selected from the biomarkers of Tables 2 and 4; (b) detecting a level of expression of the plurality of biomarkers of sensitivity and the plurality of biomarkers of resistance by performing microarray analysis or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR); and (c) administering irofulven to the patient, wherein the patient has been determined to be responsive to irofulven. 2. The method of claim 1, wherein said method further comprises (c) calculating a difference score for the patient by subtracting the mean expression levels of the plurality of biomarkers of resistance from the mean expression levels of the plurality of biomarkers of sensitivity. 3. A method of treating cancer in a human patient in need thereof comprising administering irofulven to the patient, wherein the patient has been determined to be responsive to irofulven according to a method comprising: (a) contacting a sample from the patient comprising one or more nucleic acid molecules with a device comprising: i) single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of a plurality of biomarkers of sensitivity selected from the biomarkers of Tables 1 and 3; and ii) single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of a plurality of biomarkers of resistance selected from the biomarkers of Tables 2 and 4; and (b) detecting a level of expression of the plurality of biomarkers of sensitivity and the plurality of biomarkers of resistance by performing microarray analysis or quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). 4. The method of claim 3, further comprising administering one or more additional therapies to the patient prior to, concurrently with, or after administration of irofulven. 5. The method of claim 3, wherein irofulven is administered by intravenous infusion. 6. The method of claim 5, comprising administering irofulven to the patient in a treatment regimen at least once per week for at least two weeks and/or on day 1 and day 8 of a 3 week treatment regimen. 7. The method of claim 6, wherein irofulven is administered to the patient at a dose of about 0.2 mg/kg to about 0.6 mg/kg. 8. The method of claim 7, wherein irofulven is administered at a dose of about 0.45 mg/kg. 9. The method of claim 1, wherein the contacting step (a) and the detecting step (b) occur prior to, concurrent with, or after administration of irofulven to the patient, and/or wherein the contacting step (a) and the detecting step (b) occur two or more times. 10. The method of claim 3, wherein the contacting step (a) and the detecting step (b) occur prior to, concurrent with, or after administration of irofulven to the patient, and/or wherein the contacting step (a) and the detecting step (b) occur two or more times during treatment with irofulven. 11. The method of claim 1, wherein one or more of the cancer therapies comprises surgery, radiation, or a therapeutic agent. 12. The method of claim 1, wherein the plurality of biomarkers of sensitivity are selected from ATP1B1 (SEQ ID NO: 201 or 219), UCHL1 (SEQ ID NO: 202), PTGR1 (SEQ ID NO: 203 or 210), NME7 (SEQ ID NO: 204), PLS3 (SEQ ID NO: 205), S100A10 (SEQ ID NO: 206), CD24 (SEQ ID NO: 207, 209, or 220), NQO1 (SEQ ID NO: 208 or 216), MYOF (SEQ ID NO: 211), LAPTM4B (SEQ ID NO: 212), CALD1 (SEQ ID NO: 213), PDGFC (SEQ ID NO: 214), BASP1 (SEQ ID NO: 215), ID1 (SEQ ID NO: 217), and GJA1 (SEQ ID NO: 218) and/or the plurality of biomarkers of resistance are selected from IGLC1 (SEQ ID NO: 301, 302, 303, or 318), LAPTM5 (SEQ ID NO: 304 or 338), ARHGDIB (SEQ ID NO: 305 or 311), SLC43A3 (SEQ ID NO: 307), LCP1 (SEQ ID NO: 308), HCLS1 (SEQ ID NO: 309), CD53 (SEQ ID NO: 310), MZB1 (SEQ ID NO: 313), RASSF5 (SEQ ID NO: 314 or 386), FAM46C (SEQ ID NO: 315), RCSD1 (SEQ ID NO: 316), IGJ (SEQ ID NO: 317), LPXN (SEQ ID NO: 319), ITGB7 (SEQ ID NO: 320), and GTSF1 (SEQ ID NO: 321). 13. The method of claim 1, wherein the device is a microarray. 14. The method of claim 1, wherein the device is for performing a qRT-PCR reaction. 15. The method of claim 1, wherein the level of expression of the plurality of biomarkers of sensitivity is determined by detecting the level of mRNA transcribed from genes encoding the plurality of biomarkers of sensitivity. 16. The method of claim 1, wherein the level of expression of the plurality of biomarkers of resistance is determined by detecting the level of mRNA transcribed from genes encoding the plurality of biomarkers of resistance. 17. The method of claim 1, wherein the cancer is selected from a solid tumor cancer and a hematological cancer. 18. The method of claim 1, wherein the cancer is selected from the group consisting of prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), cervical cancer, renal cell carcinoma (RCC), esophageal cancer, melanoma, glioma, pancreatic cancer, gastrointestinal stromal tumors (GIST), sarcoma, estrogen receptor-positive (ERpos) breast cancer, non-small cell lung carcinoma (NSCLC), colon cancer, bladder cancer, squamous cell carcinoma of the head and neck (SCCHN), acute myelogenous leukemia (AML), acute lympho-blastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), chronic myelogenous leukemia-chronic phase (CMLCP), diffuse large B-cell lymphoma (DLBCL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and Hodgkin's lymphoma. 19. The method of claim 3, wherein: (a) the sample from the patient is a tumor sample; (b) the patient exhibits cancer relapse after treatment with a therapeutic agent other than irofulven; (c) the patient exhibits cancer relapse prior to treatment with irofulven; or (d) the patient has not previously been administered a treatment for cancer. 20. The method of claim 1, wherein irofulven is administered at a dose of about 0.2 mg/kg to about 0.6 mg/kg. 21. The method of claim 4, wherein one or more of the additional therapies comprises surgery, radiation, or a therapeutic agent. 22. The method of claim 21, wherein the therapeutic agent is selected from the group consisting of docetaxel, cabazitaxel, mitoxantrone, estramustine, prednisone, carboplatin, bevacizumab, paclitaxel, gemcitabine, doxorubicin, topotecan, etoposide, tamoxifen, letrozole, sorafenib, fluorouracil, capecitabine, oxaliplatin, interferon-alpha, 5-fluorouracil (5-FU), a histone deacetylase (HDAC) inhibitor, ipilimumab, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, dexamethasone, cyclophosphamide, vincristine, melphalan, tegafur, irinotecan, cetuximab, leucovorin, SN-38, everolimus, temsirolimus, bleomycin, lomustine, depsipeptide, erlotinib, cisplatin, busulfan, epirubicin, arsenic trioxide, bendamustine, fulvestrant, teniposide, adriamycin, decitabine, estramustine, azaguanine, aclarubicin, mitomycin, paclitaxel, taxotere, APO010, ara-c, methylprednisolone, methotrexate, methyl-gag, belinostat, idarubicin, IL4-PR38, valproic acid, all-trans retinoic acid (ATRA), cytoxan, suberoylanilide hydroxamic acid, leukeran, fludarabine, vinblastine, dacarbazine, hydroxyurea, tegafur, daunorubicin, mechlorethamine, streptozocin, carmustine, mercaptopurine, dactinomycin, tretinoin, ifosfamide, floxuridine, thioguanine, PSC 833, herceptin, celecoxib, iressa, anastrozole, and rituximab. 23. The method of claim 6, wherein the treatment regimen is repeated two to twenty times. 24. The method of claim 3, wherein the plurality of biomarkers of sensitivity are selected from two or more of ATP1B1 (SEQ ID NO: 201 or 219), UCHL1 (SEQ ID NO: 202), PTGR1 (SEQ ID NO: 203 or 210), NME7 (SEQ ID NO: 204), PLS3 (SEQ ID NO: 205), S100A10 (SEQ ID NO: 206), CD24 (SEQ ID NO: 207, 209, or 220), NQO1 (SEQ ID NO: 208 or 216), MYOF (SEQ ID NO: 211), LAPTM4B (SEQ ID NO: 212), CALD1 (SEQ ID NO: 213), PDGFC (SEQ ID NO: 214), BASP1 (SEQ ID NO: 215), ID1 (SEQ ID NO: 217), and GJA1 (SEQ ID NO: 218) and/or the plurality of biomarkers of resistance are selected from two or more of IGLC1 (SEQ ID NO: 301, 302, 303, or 318), LAPTM5 (SEQ ID NO: 304 or 338), ARHGDIB (SEQ ID NO: 305 or 311), SLC43A3 (SEQ ID NO: 307), LCP1 (SEQ ID NO: 308), HCLS1 (SEQ ID NO: 309), CD53 (SEQ ID NO: 310), MZB1 (SEQ ID NO: 313), RASSF5 (SEQ ID NO: 314 or 386), FAM46C (SEQ ID NO: 315), RCSD1 (SEQ ID NO: 316), IGJ (SEQ ID NO: 317), LPXN (SEQ ID NO: 319), ITGB7 (SEQ ID NO: 320), and GTSF1 (SEQ ID NO: 321). 25. The method of claim 3, wherein the cancer is selected from a solid tumor cancer and a hematological cancer. 26. The method of claim 3, wherein the cancer is selected from the group consisting of prostate cancer, ovarian cancer, hepatocellular carcinoma (HCC), cervical cancer, renal cell carcinoma (RCC), esophageal cancer, melanoma, glioma, pancreatic cancer, gastrointestinal stromal tumors (GIST), sarcoma, estrogen receptor-positive (ERpos) breast cancer, non-small cell lung carcinoma (NSCLC), colon cancer, bladder cancer, squamous cell carcinoma of the head and neck (SCCHN), acute myelogenous leukemia (AML), acute lympho-blastic leukemia (ALL), chronic lymphocytic leukemia (CLL), myelodysplastic syndrome (MDS), chronic myelogenous leukemia-chronic phase (CMLCP), diffuse large B-cell lymphoma (DLBCL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and Hodgkin's lymphoma. 27. The method of claim 2, wherein: i) the difference score is substantially similar to a difference score of a patient known to be sensitive to irofulven; and/or ii) the difference score is substantially dissimilar to a difference score of a patient known to be resistant to irofulven. 28. The method of claim 3, wherein said method further comprises (c) calculating a difference score for the patient by subtracting the mean expression levels of the plurality of biomarkers of resistance from the mean expression levels of the plurality of biomarkers of sensitivity. 29. The method of claim 28, wherein: i) the difference score is substantially similar to a difference score of a patient known to be sensitive to irofulven; and/or ii) the difference score is substantially dissimilar to a difference score of a patient known to be resistant to irofulven.

Details for Patent 9,725,769

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