Combination therapies and methods of use thereof for treating cancer
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.
1. A method of treating a patient with cancer comprising administering to the patient an effective amount of abiraterone or abiraterone acetate in combination with an effective amount of a polo-like kinase inhibitor (PLK),
wherein the abiraterone or abiraterone acetate and the polo-like kinase inhibitor are administered simultaneous or wherein the abiraterone or abiraterone acetate is administered to the patient 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, prior to administration of the polo-like kinase inhibitor to the patient, and wherein administration of the combination of abiraterone or abiraterone acetate and the polo-like kinase inhibitor is effective to reduce cancer cell proliferation or viability in the patient to a greater degree than administering to the patient the same amount of abiraterone or abiraterone acetate alone or the same amount of polo-like kinase inhibitor alone.
2. The method of claim 1 , wherein the dosage of abiraterone acetate is 250 mg-1,500 mg.
3. The method of claim 1 , wherein the class of polo-like kinase inhibitor 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.
4. The method of claim 3 , wherein the polo-like kinase 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.
5. The method of claim 4 , wherein the polo-like kinase inhibitor inhibitor is BI2536.
6. The method of claim 5 , wherein the dosage of BI25236 is between one and 500 mg.
7. The method of claim 1 , wherein the cancer cells are selected from the group consisting of breast cancer cells, prostate cancer cells and pancreatic cancer cells.
8. The method 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 abiraterone or abiraterone acetate alone or the polo-like kinase inhibitor alone.
9. The method of claim 1 , wherein the cancer cells are insensitive to abiraterone when abiraterone acetate is administered without co-administration of the polo-like kinase inhibitor.
10. The method of claim 1 , wherein the abiraterone or abiraterone acetate is administered to the subject 1, 2, 3, 4, 5, 6, 8, 10, 12, 18, or 24 hours, prior to administration of the polo-like kinase inhibitor to the subject.
11. The method of claim 1 , 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.
12. The method of claim 11 , wherein one additional active agent is the steroid prednisone.
13. The method of claim 11 , wherein one additional active agent is the chemotherapeutic agent is docetaxel.
14. The method of claim 1 , further comprising surgery or radiation therapy.
15. The method of claim 1 , 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).
16. The method of claim 1 , 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.
17. The method of claim 1 , 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.
18. The method of claim 1 , wherein the cancer is selected from the group consisting of prostate cancer, breast cancer and pancreatic cancer.