Combination therapies and methods of use thereof for treating cancer

Abstract

Pharmaceutical compositions including an effective amount of an antiandrogen or androgen antagonist in combination with a Plk inhibitor and methods of use thereof for treating cancer are disclosed. Administration of the combination of the active agents can be effective to reduce cancer cell proliferation or viability in a subject with cancer to the same degree, or a greater degree than administering to the subject the same amount of either active agent alone. The active agents can be administered together or separately. Methods of selecting and treating subjects with cancers, particular prostate cancers including castration resistant prostate cancer, breast cancers, particularly androgen receptor positive breast cancers, and pancreatic cancers are also provided.

We claim: 
     
         1 . A pharmaceutical composition comprising an effective amount of the combination of an antiandrogen or androgen antagonist and a Plk inhibitor, wherein administration of the pharmaceutical composition reduces cancer cell proliferation or reduces cancer cell viability, or reduces both cancer cell viability and proliferation in a subject with cancer to a greater degree than administering to the subject the same amount of antiandrogen or androgen antagonist alone or the same amount of Plk inhibitor alone. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the reduction in cancer cell proliferation or viability in the subject with cancer is more than the additive reduction achieved by administering the antiandrogen or androgen antagonist alone or the Plk inhibitor alone. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the antiandrogen or androgen antagonist is selected from the group consisting of abiraterone, TOK-001, ARN 509 and mixtures thereof. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the antiandrogen or androgen antagonist is abiraterone, or a prodrug, analog, or derivative, or pharmaceutically acceptable salt thereof. 
     
     
         5 . The pharmaceutical composition of  claim 4 , wherein the dosage of abiraterone acetate is 250 mg-1,500 mg. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the class of Plk inhibitors is selected from the group consisting of dihydropteridinones, pyridopyrimidines, aminopyrimidines, substituted thiazolidinones, pteridine derivatives, dihydroimidazo[1,5-f]pteridines, metasubstituted thiazolidinones, benzyl styryl sulfone analogues, stilbene derivatives, and combinations thereof. 
     
     
         7 . The pharmaceutical composition of  claim 6 , wherein the P1K inhibitor is selected from the group consisting of BI2536, Volasertib (BI 6727), GSK461364, HMN-176, HMN-214, rigosertib (ON-01910), MLN0905, TKM-080301, TAK-960, NMS-1286937 or Ro3280. 
     
     
         8 . The pharmaceutical composition of  claim 7 , wherein the Plk1 inhibitor is BI2536. 
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the dosage of BI25236 is 1 mg-500 mg. 
     
     
         10 . The pharmaceutical composition of  claim 1 , further comprising prednisone. 
     
     
         11 . The pharmaceutical composition of  claim 1 , wherein the cancer cells are selected from the group consisting of breast cancer cells, prostate cancer cells and pancreatic cancer cells 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the cancer cells are insensitive to abiraterone when abiraterone acetate is administered without co-administration of the Plk inhibitor. 
     
     
         13 . A method of treating cancer comprising administering to a subject an effective amount of an antiandrogen or androgen antagonist in combination with an effective amount of a Plk inhibitor, wherein administration of the combination the antiandrogen or androgen antagonist and the Plk inhibitor reduces cancer cell proliferation or viability in a subject with cancer to a greater degree than administering to the subject the same amount of antiandrogen or androgen antagonist alone or the same amount of Plk inhibitor alone. 
     
     
         14 . The method of  claim 13 , wherein the reduction in cancer cell proliferation or viability in the subject with cancer is more than the additive reduction achieved by administering the antiandrogen or androgen antagonist alone or the Plk inhibitor alone. 
     
     
         15 . The method of  claim 13 , wherein the cancer cells are insensitive to abiraterone when abiraterone acetate is administered without co-administration of the Plk inhibitor. 
     
     
         16 . The method of  claim 13 , wherein the antiandrogen or androgen antagonist is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, 1, 2, 3, 4, 5, 6, or 7 days, 1, 2, 3, or 4 weeks, or any combination thereof prior to administration of the Plk inhibitor to the subject. 
     
     
         17 . The method of  claim 13 , wherein the Plk inhibitor is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, 1, 2, 3, 4, 5, 6, or 7 days, 1, 2, 3, or 4 weeks, or any combination thereof prior to administration of the antiandrogen or androgen antagonist to the subject. 
     
     
         18 . The method of  claim 13 , further comprising administering to the subject one or more additional active agents selected from the group consisting of a steroid, a chemotherapeutic agent, an anti-infective agent, and combinations thereof. 
     
     
         19 . The method of  claim 18 , wherein one additional active agent is the steroid prednisone. 
     
     
         20 . The method of  claim 18 , wherein one additional active agent is the chemotherapeutic agent is docetaxel. 
     
     
         21 . The method of  claim 13 , further comprising surgery or radiation therapy. 
     
     
         22 . The method of  claim 13 , wherein the cancer to be treated is characterized by expression of genes involved in the Retinoic Acid Receptor (RA) signaling pathway. 
     
     
         23 . The method of  claim 22 , wherein one or more genes involved in retinoic acid signaling are selected from the group consisting of Retinoic Acid Receptor Alpha (RARA); Retinoic Acid Receptor Gamma (RARG); Retinol Dehydrogenase (ADH4); and Retinaldehyde Reductase (DHRS3). 
     
     
         24 . The method of  claim 13 , wherein the cancer is characterized by expression, over-expression or up-regulation of genes driven by the Nrf1/2 or Elk1 transcription factors following treatment. 
     
     
         25 . The method of  claim 13 , further comprising the step of selecting a subject having a cancer characterized by expression of genes involved in the Retinoic Acid Receptor (RA) signaling pathway. 
     
     
         26 . A method of treating cancer in a subject having cancer cells that exhibit expression of one or more genes involved in the retinoic acid signaling pathway, comprising
 administering to the subject an effective amount of an antiandrogen or androgen antagonist in combination with an effective amount of a Plk inhibitor, wherein administration of the combination the antiandrogen or androgen antagonist and the Plk inhibitor reduces cancer cell proliferation or cancer cell viability in the subject.   
     
     
         27 . The method of  claim 26 , wherein one or more genes involved in retinoic acid signaling are selected from the group consisting of Retinoic Acid Receptor Alpha (RARA); Retinoic Acid Receptor Gamma (RARG); Retinol Dehydrogenase (ADH4); and Retinaldehyde Reductase (DHRS3). 
     
     
         28 . The method of  claim 26 , wherein the cancer is selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer.