Hormone suppression therapy and docetaxel chemotherapy are among the most effective treatments for advanced prostate cancer. Abiraterone is a novel, highly potent hormone-suppressing drug, and there has been great enthusiasm for combining next-generation hormonal agents with taxanes. However, the optimal setting, sequence, or timing of these agents with taxane therapy has not been established. The experiments in this proposal will inform the optimal sequencing of taxane and abiraterone therapy in patients with castration-resistant prostate cancer. Prostate cancer xenografts will be treated with docetaxel followed by abiraterone, abiraterone + docetaxel, or abiraterone followed by docetaxel. The impact of treatment sequence and combination on tumor growth, androgen levels, and splice variant production will be evaluated and correlated with sensitivity to docetaxel inhibition. Determining whether sequential therapy with abiraterone to achieve suppression of tumor androgens and induction of androgen receptor splice variants followed by taxane therapy is superior to concurrent therapy will be critical to informing clinical practice. |
