One American man dies every 16 minutes from castration resistant prostate cancers (CRPCs) that continue to grow despite treatments that lower the male hormones that drive these tumors. These patients are the focus of this application. Despite achieving low blood levels of male hormones with anti-hormonal therapies, recent work demonstrates that male hormones persist within CRPC tumors and drive tumor growth. Hence, male hormones remain a critical therapeutic target in CRPC. Indeed, the novel drug MDV3100 interferes with male hormones that persist within CRPC tumors. In a recent clinical trial, MDV3100 treatment reduced tumor growth and improved survival by 5 months -- the largest improvement in survival for any drug tested in CRPC patients to date. However, one-half of patients' tumors fail to respond to MDV3100 treatment. Furthermore, all tumors eventually progress despite continuous MDV3100 treatment. Currently, we have little understanding about how CRPCs grow and kill patients despite MDV3100 treatment. The goal of this proposal is to shed significant light on this problem of resistance to treatment with MDV3100 or drugs like it.

We will accomplish this by measuring the differences in gene expression within prostate cancer cell lines and CRPC patient tumors that contribute to MDV3100 resistance. Our integrative approach will combine work in the laboratory to identify gene changes present in prostate cancer cells prior to MDV3100 treatment that mediate MDV3100 resistance. We will confirm the importance of these gene changes by disrupting them in prostate cancer cell lines and determining if this enhances prostate cancer cell killing with MDV3100 treatment. We will also measure these gene changes in tumor material obtained from CRPC patients prior to treatment with MDV3100 on a clinical trial. This will enable us to determine if these genes changes correlate with resistance to MDV3100 treatment. Finally, we will also perform a subsequent biopsy on these MDV3100-treated patients. This will enable us to identify gene changes between the pre-treatment biopsy and the on-treatment biopsy that cause CRPCs to eventually grow despite MDV3100 treatment in patients. Our results will inform rationally designed clinical trials that combine MDV3100 with other drugs that suppress MDV3100 resistance mechanisms we identify herein. Clinical trials based on the preliminary studies from this proposal are predicted to convert MDV3100-resistant CRPC tumors into MDV3100-sensitive tumors and to further increase the duration of MDV3100 tumor response and patient survival.