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.

1 . A method for detecting expression of a biomarker in a patient having cancer that is resistant to one or more cancer therapies other than irofulven comprising:
 (a) contacting a sample from the patient comprising one or more nucleic acid molecules with a device comprising:
 i) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of sensitivity selected from the biomarkers of Tables 1 and 3; and/or 
 ii) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of resistance selected from the biomarkers of Tables 2 and 4; and 
   (b) detecting a level of expression of one or more of the biomarkers of sensitivity and/or one or more of the biomarkers of resistance by performing microarray analysis or quantitative reverse transcriptase polymerase chain reaction (q RT-PCR).   
     
     
         2 . A method of determining responsiveness of a patient having cancer to irofulven comprising:
 (a) contacting a sample from the patient comprising one or more nucleic acid molecules with a device comprising:
 i) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of sensitivity selected from the biomarkers of Tables 1 and 3; and/or 
 ii) one or more single-stranded nucleic acid molecules capable of specifically hybridizing with the nucleotides of one or more biomarkers of resistance selected from the biomarkers of Tables 2 and 4; 
   (b) measuring hybridization, or an amplification product resulting from hybridization, between the one or more nucleic acid molecules from the patient and the single-stranded nucleic acid molecules of the device to detect a level of expression of one or more of the biomarkers of sensitivity and/or one or more of the biomarkers of resistance; wherein the patient is determined to be responsive to irofulven if:
 i) the level of expression of the biomarkers of sensitivity is substantially similar to the level of expression of the biomarkers of sensitivity in a cell or tissue known to be sensitive to irofulven; and/or 
 ii) the level of expression of the biomarkers of resistance is substantially dissimilar to the level of expression of the biomarkers of resistance in a cell or tissue known to be resistant to irofulven. 
   
     
     
         3 . The method of  claim 2 , wherein said method further comprises administering irofulven to the patient if:
 i) the level of expression of the biomarkers of sensitivity is substantially similar to the level of expression of the biomarkers of sensitivity in a cell or tissue known to be sensitive to irofulven; and/or   ii) the level of expression of the biomarkers of resistance is substantially dissimilar to the level of expression of the biomarkers of resistance in a cell or tissue known to be resistant to irofulven; and/or   
     
     
         4 . The method of  claim 2 , wherein said method further comprises administering one or more cancer therapies other than irofulven to the patient if:
 i) the level of expression of the biomarkers of sensitivity is substantially dissimilar to the level of expression of the biomarkers of sensitivity in a cell or tissue known to be sensitive to irofulven; and/or   ii) the level of expression of the biomarkers of resistance is substantially similar to the level of expression of the biomarkers of resistance in a cell or tissue known to be resistant to irofulven   
     
     
         5 . The method of  claim 4 , wherein one or more of the cancer therapies comprises surgery, radiation, or a therapeutic agent, and 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. 
     
     
         6 . A method of treating cancer in a patient in need thereof comprising administering irofulven to the patient, wherein the patient has been determined to be responsive to irofulven according to the method of  claim 2 . 
     
     
         7 . The method of  claim 6 , further comprising administering one or more additional therapies to the patient prior to, concurrently with, or after administration of irofulven, wherein one or more of the additional therapies comprises surgery, radiation, or a therapeutic agent, and 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. 
     
     
         8 . The method of  claim 7 , wherein irofulven is administered by intravenous infusion. 
     
     
         9 . The method of  claim 8 , 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, wherein the treatment regimen occurs. 
     
     
         10 . The method of  claim 9 , wherein the treatment regimen is repeated two to twenty times. 
     
     
         11 . The method of  claim 9 , wherein irofulven is administered to the patient at a dose of about 0.1 mg/kg to 1 mg/kg. 
     
     
         12 . The method of  claim 11 , wherein irofulven is administered to the patient at a dose of about 0.2 mg/kg to about 0.6 mg/kg. 
     
     
         13 . The method of  claim 12 , wherein irofulven is administered at a dose of about 0.45 mg/kg. 
     
     
         14 . The method of  claim 3 , wherein the contacting step (a) and the measuring step (b) occur prior to, concurrent, or after administration of irofulven to the patient, and/or wherein the contacting step (a) and the measuring step (b) occur two or more times. 
     
     
         15 . The method of  claim 6 , wherein the contacting step (a) and the measuring step (b) occur prior to, concurrent, or after administration of irofulven to the patient, and/or wherein the contacting step (a) and the measuring step (b) occur two or more times during treatment with irofulven. 
     
     
         16 . The method of  claim 1 , wherein one or more of the cancer therapies comprises surgery, radiation, or a therapeutic agent. 
     
     
         17 . The method of  claim 2 , wherein the patient is resistant to one or more cancer therapies other than irofulven wherein one or more of the cancer therapies comprises surgery, radiation, or a therapeutic agent. 
     
     
         18 . The method of  claim 1 , wherein the biomarker of sensitivity is selected from one 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 biomarker of resistance is selected from one 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). 
     
     
         19 . The method of  claim 2 , wherein the biomarker of sensitivity is selected from one 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 biomarker of resistance is selected from one 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). 
     
     
         20 . The method of  claim 1 , wherein the device is a microarray. 
     
     
         21 . The method of  claim 2 , wherein the device is a microarray. 
     
     
         22 . The method of  claim 1 , wherein the device is for performing a qRT-PCR reaction. 
     
     
         23 . The method of  claim 2 , wherein the device is for performing a qRT-PCR reaction. 
     
     
         24 . The method of  claim 1 , wherein the level of expression of one or more of the biomarkers of sensitivity and/or one or more of the biomarkers of resistance is determined by detecting the level of mRNA transcribed from one or more genes encoding one or more of the biomarkers of Tables 1-4. 
     
     
         25 . The method of  claim 2 , wherein the level of expression of one or more of the biomarkers of sensitivity and/or one or more of the biomarkers of resistance is determined by detecting the level of mRNA transcribed from one or more genes encoding one or more of the biomarkers of Tables 1-4. 
     
     
         26 . The method of  claim 1 , wherein the cancer is selected from a solid tumor cancer and a hematological cancer and/or 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 the cancer is selected from a solid tumor cancer and a hematological cancer and/or 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. 
     
     
         28 . The method of  claim 1 , 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 been administered a treatment for cancer. 
     
     
         29 . The method of  claim 2 , 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 been administered a treatment for cancer.