Methods for predicting drug responsiveness in cancer patients

Abstract

The present invention features methods, devices, and kits for detecting gene expression in a patient with a cancer or determining responsive of a patient with a cancer to a treatment, such as treatment with dovitinib or a pharmaceutically acceptable salt thereof. The invention further includes methods of treating a patient with a cancer by administering a treatment, e.g., treatment with dovitinib or a pharmaceutically acceptable salt thereof, in particular when the patient is determined to be responsive to the treatment based on the expression of the biomarkers described herein.

1 . A method of determining responsiveness of a subject with a cancer to dovitinib or a pharmaceutically acceptable salt thereof comprising:
 (a) contacting a sample from the subject 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 Table 2; 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 Table 3; and 
   (b) measuring hybridization between the one or more nucleic acid molecules from the sample and the single-stranded nucleic acid molecules of the device to detect a level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance.   
     
     
         2 . The method of  claim 1 , wherein the subject is determined to be responsive to dovitinib or a pharmaceutically acceptable salt thereof if:
 (i) the level of expression of the one or more biomarkers of sensitivity is substantially similar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be sensitive to dovitinib or a pharmaceutically acceptable salt thereof;   (ii) the level of expression of the one or more biomarkers of resistance is substantially similar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be sensitive to dovitinib or a pharmaceutically acceptable salt thereof;   (iii) the level of expression of the one or more biomarkers of sensitivity is substantially dissimilar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be resistant to dovitinib or a pharmaceutically acceptable salt thereof; and/or   (iv) the level of expression of the one or more biomarkers of resistance is substantially dissimilar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be resistant to dovitinib or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The method of  claim 1 , further comprising administering dovitinib or a pharmaceutically acceptable salt thereof to the subject. 
     
     
         4 . The method of  claim 1 , further comprising administering one or more cancer therapies other than dovitinib or a pharmaceutically acceptable salt thereof to the subject, wherein, optionally, the one or more cancer therapies comprises surgery, radiation, or a therapeutic agent. 
     
     
         5 . The method of  claim 2 , wherein:
 (i) sensitivity of a cell or tissue known to be sensitive to dovitinib or a pharmaceutically acceptable salt thereof is based on G150 data of NCI60 cell lines; and/or   (ii) resistance of a cell or tissue known to be resistant to dovitinib or a pharmaceutically acceptable salt thereof is based on G150 data of NCI60 cell lines.   
     
     
         6 . The method of  claim 4 , wherein the therapeutic agent is selected from the group consisting of a histone deacetylase (HDAC) inhibitor, an immune checkpoint inhibitor, a cyclin-dependent kinase (CDK) inhibitor, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, prednisone, dexamethasone, cyclophosphamide, vincristine, doxorubicin, melphalan, capecitabine, tegafur, irinotecan, oxaliplatin, cetuximab, leucovorin, SN-38, everolimus, temsirolimus, bleomycin, lomustine, depsipeptide, carboplatin, erlotinib, gemcitabine, mitoxantrone, cisplatin, busulfan, epirubicin, arsenic trioxide, bendamustine, fulvestrant, teniposide, adriamycin, decitabine, estramustine, etoposide, azaguanine, aclarubicin, mitoxantrone, mitomycin, paclitaxel, taxotere, Irofulven, 5-FU, ara-c, methylprednisolone, methotrexate, methyl-gag, belinostat, carboplatin, idarubicin, IL4-PR38, valproic acid, all-trans retinoic acid (ATRA), cytoxan, topotecan, suberoylanilide hydroxamic acid, leukeran, fludarabine, vinblastine, dacarbazine, hydroxyurea, tegafur, daunorubicin, mechlorethamine, streptozocin, carmustine, mercaptopurine, dactinomycin, tretinoin, ifosfamide, tamoxifen, floxuridine, thioguanine, PSC 833, herceptin, bevacizumab, celecoxib, iressa, anastrozole, letrozole, and rituximab. 
     
     
         7 . The method of  claim 6 , wherein the immune checkpoint inhibitor is a PD1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor. 
     
     
         8 . A method of treating a cancer in a subject in need thereof comprising administering dovitinib or a pharmaceutically acceptable salt thereof to the subject, wherein the subject has been determined to be responsive to dovitinib or the pharmaceutically acceptable salt thereof according to the method of  claim 1 . 
     
     
         9 . A method of treating a subject with a cancer, the method comprising:
 (a) contacting a sample from the subject 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 Table 2; 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 Table 3; 
   (b) measuring hybridization between the one or more nucleic acid molecules from the sample and the single-stranded nucleic acid molecules of the device to detect a level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance; and   (c) administering dovitinib or a pharmaceutically acceptable salt thereof to the subject.   
     
     
         10 . The method of  claim 9 , wherein the subject is administered dovitinib or the pharmaceutically acceptable salt thereof if:
 (i) the level of expression of the one or more biomarkers of sensitivity is substantially similar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be sensitive to dovitinib or a pharmaceutically acceptable salt thereof;   (ii) the level of expression of the one or more biomarkers of resistance is substantially similar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be sensitive to dovitinib or a pharmaceutically acceptable salt thereof;   (iii) the level of expression of the one or more biomarkers of sensitivity is substantially dissimilar to the level of expression of the one or more biomarkers of sensitivity in a cell or tissue known to be resistant to dovitinib or a pharmaceutically acceptable salt thereof; and/or   (iv) the level of expression of the one or more biomarkers of resistance is substantially dissimilar to the level of expression of the one or more biomarkers of resistance in a cell or tissue known to be resistant to dovitinib or a pharmaceutically acceptable salt thereof.   
     
     
         11 . The method of  claim 10 , wherein:
 (i) sensitivity of a cell or tissue known to be sensitive to dovitinib or a pharmaceutically acceptable salt thereof is based on G150 data of NCI60 cell lines; and/or   (ii) resistance of a cell or tissue known to be resistant to dovitinib or a pharmaceutically acceptable salt thereof is based on G150 data of NCI60 cell lines.   
     
     
         12 . The method of  claim 11 , further comprising administering one or more additional therapies to the subject prior to, concurrently with, or after administration of dovitinib or the pharmaceutically acceptable salt thereof, wherein, optionally, the one or more additional therapies comprises surgery, radiation, or a therapeutic agent. 
     
     
         13 . The method of  claim 12 , wherein the therapeutic agent is selected from the group consisting of a histone deacetylase (HDAC) inhibitor, an immune checkpoint inhibitor, an antiestrogen, an aromatase inhibitor, an antigonadotropin, a proteasome inhibitor, an immunomodulator, a glucocorticoid, a folic acid, a monoclonal antibody, and an antineoplastic agent, wherein optionally the therapeutic agent is fulvestrant, ipilimumab, a cyclin-dependent kinase (CDK) inhibitor, bortezomib, carfilzomib, thalidomide, lenalidomide, pomalidomide, prednisone, dexamethasone, cyclophosphamide, vincristine, doxorubicin, melphalan, capecitabine, tegafur, irinotecan, oxaliplatin, cetuximab, leucovorin, SN-38, everolimus, temsirolimus, bleomycin, lomustine, depsipeptide, carboplatin, erlotinib, gemcitabine, mitoxantrone, cisplatin, busulfan, epirubicin, arsenic trioxide, bendamustine, teniposide, adriamycin, decitabine, estramustine, etoposide, azaguanine, aclarubicin, mitoxantrone, mitomycin, paclitaxel, taxotere, Irofulven, 5-FU, ara-c, methylprednisolone, methotrexate, methyl-gag, belinostat, carboplatin, idarubicin, IL4-PR38, valproic acid, all-trans retinoic acid (ATRA), cytoxan, topotecan, suberoylanilide hydroxamic acid, leukeran, fludarabine, vinblastine, dacarbazine, hydroxyurea, tegafur, daunorubicin, mechlorethamine, streptozocin, carmustine, mercaptopurine, dactinomycin, tretinoin, ifosfamide, tamoxifen, clomifene, raloxifene, floxuridine, thioguanine, PSC 833, herceptin, bevacizumab, celecoxib, iressa, anastrozole, letrozole, or rituximab. 
     
     
         14 . The method of  claim 13 , wherein the therapeutic agent is an immune checkpoint inhibitor, wherein optionally the immune checkpoint inhibitor is a PD1 inhibitor, a PD-L1 inhibitor, or a CTLA-4 inhibitor, an antiestrogen, fulvestrant, an aromatase inhibitor, or an antigonadotropin. 
     
     
         15 . The method of  claim 1 , further comprising determining an expression level of one or more biomarkers of responsiveness to an immune checkpoint inhibitor,
 wherein, optionally, the one or more biomarkers are selected from the group consisting of PD-1, PD-L1, CTLA-4, and FAS receptor, such as a three-gene biomarker of PD-1, PD-L1, and FAS receptor.   
     
     
         16 . The method of  claim 15 , wherein the method further comprises administering the immune checkpoint inhibitor to the subject that has been determined to be responsive to the immune checkpoint inhibitor. 
     
     
         17 . The method of  claim 3 , comprising:
 a) administering dovitinib or the pharmaceutically acceptable salt thereof to the subject two or more times;   b) administering dovitinib or the pharmaceutically acceptable salt thereof to the subject one or more times daily, weekly, every two weeks, every three weeks, or monthly;   c) administering dovitinib or the pharmaceutically acceptable salt thereof to the subject once daily for five days; or   d) administering dovitinib or the pharmaceutically acceptable salt thereof to the subject in an ON: OFF schedule.   
     
     
         18 . The method of  claim 17 , comprising administering dovitinib or the pharmaceutically acceptable salt thereof to the subject in a five days ON: two days OFF schedule. 
     
     
         19 . The method of  claim 3 , wherein dovitinib or the pharmaceutically acceptable salt thereof is administered to the subject:
 a) at a dose of about 5-5000 mg;   b) at a dose of about 10 mg, 50 mg, 200 mg, or 500 mg;   c) at a dose of about 50-800 mg;   d) at a dose of about 500 mg once daily;   e) at a dose of about 500 mg once daily for five days;   f) at a dose of about 500 mg once daily in a five days ON: two days OFF schedule.   
     
     
         20 . The method of  claim 1 , wherein the device is a microarray, wherein, optionally, the microarray is a deoxyribonucleic acid (DNA)-based platform. 
     
     
         21 . The method of  claim 1 , wherein:
 a) the device comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least ten, or more single-stranded nucleic acid molecules of (i) and/or (ii);   b) the one or more single-stranded nucleic acid molecules of the device have a length in the range of 10-100 nucleotides;   c) the method comprises converting the level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance into a mean score, wherein the mean score indicates the responsiveness of the subject to dovitinib or a pharmaceutically acceptable salt thereof;   d) the level of expression of the one or more biomarkers of sensitivity and/or the one or more biomarkers of resistance is determined by microarray analysis or nucleic acid amplification methods.   
     
     
         22 . The method of  claim 21 , further comprising subtracting the mean score for the one or more biomarkers of resistance from the mean score for the one or more biomarkers of sensitivity to obtain a difference score, wherein the difference score indicates the responsiveness of the subject to dovitinib or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 21 , wherein the mean score and/or the difference score above a cutoff value indicates that the subject is responsive to dovitinib or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of  claim 23 , wherein the cutoff value is established as the 50th percentile, or 60th percentile, or 70th percentile, or 80th percentile, or 90th percentile or greater in a reference population, such as a sample(s) from a tumor of the same type as that of the subject. 
     
     
         25 . The method of  claim 1 , wherein:
 (i) the level of expression of the biomarkers of sensitivity is determined by detecting the level of mRNA transcribed from a gene coding one or more of the biomarkers of Table 2; and/or   (ii) the level of expression of the biomarkers of resistance is determined by detecting the level of mRNA transcribed from a gene coding one or more of the biomarkers of Table 3.   
     
     
         26 . The method of  claim 1 , wherein:
 a)   (i) the biomarkers of sensitivity are selected from at least 5, at least 10, at least 15, at least 20, at least 25, or at least 27 of the biomarkers of Table 2; and/or   (ii) the biomarkers of resistance are selected from at least 5, at least 10, at least 15, at least 20, at least 25, or at least 27 of the biomarkers of Table 3;   b) the biomarkers of sensitivity are selected from one or more of SEQ ID NOs: 1-15 and/or one or more of SEQ ID NOs: 16-30;   c) the biomarkers of resistance are selected from one or more of SEQ ID NOs: 31-45 and/or one or more of SEQ ID NOs: 46-58; or   d)   (i) the biomarker of sensitivity is DDIT4 (SEQ ID NO: 1); and/or   (ii) the biomarker of resistance is SCAMP3 (SEQ ID NO: 31).   
     
     
         27 . The method of  claim 1 , wherein the cancer is selected from a solid tumor cancer and a hematological cancer. 
     
     
         28 . The method of  claim 1 , wherein the cancer is selected from the group consisting of multiple myeloma, breast cancer, 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), Hodgkin's lymphoma, hepatocellular carcinoma (HCC), cervical cancer, prostate cancer, kidney cancer, renal cell carcinoma (RCC), esophageal cancer, melanoma, glioma, pancreatic cancer, ovarian cancer, gastrointestinal stromal tumors (GIST), sarcoma, breast cancer, estrogen receptor-positive (ERpos) breast cancer, metastatic breast cancer, endometrial cancer, lung cancer, non-small cell lung carcinoma (NSCLC), mesothelioma, intestinal cancer, colon cancer, bladder cancer, adrenal cancer, gallbladder cancer, and squamous cell carcinoma of the head and neck (SCCHN). 
     
     
         29 . The method of  claim 1 , wherein the subject has recurrence of cancer. 
     
     
         30 . The method of  claim 1 , wherein the sample from the subject is a tumor sample.