Optimizing Treatment of Advanced Prostate Cancer and Exploiting Mechanisms Driving Castration Resistance

摘要

Castration resistant prostate cancer (CRPC) ubiquitously displays increased expression of the AR and AR target genes, reflecting the critical importance of this pathway in prostate cancer progression. As novel agents which potently inhibit the AR pathway become clinically available, it will be critical to understand how severe shutdown of the AR pathway impacts tumor cell biology and how this will alter the natural history of CRPC. This proposal investigates the impact of maximal intra-tumoral androgen pathway suppression on prostate tumor regression and recurrence, and seeks to determine whether specific resistance mechanisms identified at tumor progression will reflect the efficacy of androgen axis suppression and/or predict sensitivity to subsequent therapy. Our studies assess whether tumors recurring after the most stringent AR pathway blockade pharmacologically available will continue to retain a dependence on the AR axis or will exhibit an AR null phenotype driven by non-AR directed resistance mechanisms. To date we have completed enrollment into our xenograft study of maximal androgen suppression, which uses the well defined LuCaP35 prostate cancer xenograft and three tiers of progressive AR axis suppression, as well as enrollment into one of two studies of high dose testosterone replacement therapy. Analysis of tumor growth and regression, as well as molecular analyses are ongoing and will be reported in years 2 and 3 of the award as per the Statement of Work.