Method of treatment of prostate cancer with androgen receptor and glucocorticoid receptor antagonists
Methods are directed to the treatment of subjects with prostate cancer, in particular those with castration resistant prostate cancer, with glucocorticoid receptor antagonists. The prostate cancer may be one that has become resistant to androgen deprivation therapy, for example, by increase in glucocorticoid receptor expression and/or activity.
1. A method of treating prostate cancer in a subject comprising administering to said subject therapeutically effective amounts of an androgen receptor (AR) antagonist and a glucocorticoid receptor (GR) antagonist.
2. A method of claim 1 wherein the prostate cancer is castration resistant with an elevated glucocorticoid receptor level and the AR antagonist and GR antagonist are administered in amounts that provide a synergistic reduction of prostate cancer cells in the subject.
3. The method of claim 2 , wherein the AR antagonist is MDV3100, ARN-509, flutamide, bicalutamide, nilutamide, or cyproterone acetate.
4. The method of claim 2 , wherein said GR antagonist is mifepristone.
5. The method of claim 2 wherein the GR antagonist is selected from the group consisting of pyrimidinediones, azadecalins, and aryl pyrazolo azadecalins.
6. The method of claim 2 , wherein said subject has previously been or is being treated with androgen deprivation therapy.
7. The method of claim 6 , wherein said androgen deprivation therapy comprises treatment with leuprolide goserelin, triptorelin, histrelin, or surgical castration.
8. The method of claim 6 , said androgen deprivation therapy is an androgen synthesis inhibitor.
9. The method of claim 8 , wherein the androgen synthesis inhibitor is selected from ketococonazole, abiraterone, TAK-700 and TOK001.
10. The method of claim 2 , wherein said GR antagonist is administered systemically, regionally or locally to a tumor site.
11. The method of claim 2 , further comprising assessing GR expression in a prostate cancer tissue of said subject.
12. The method of claim 2 , further comprising assessing androgen receptor expression in a prostate cancer tissue of said subject.
13. The method of claim 2 , wherein said prostate cancer is metastatic or recurrent.