Grant: Project Grant

Prostate cancer (PCa) is the most commonly diagnosed non-skin cancer in Canadian men and one of the leading causes of cancer-related death. In almost all patients, the proliferation and growth of PCa is driven by the androgen receptor (AR). Given this critical role, inhibiting the AR is the standard of care following surgery or radiotherapy. The effectiveness of current therapeutics is usually temporary, with the cancer eventually developing drug resistance. There are no curative treatment options for resistant PCa and these patients have a median life-expectancy of only 20 months. Currently, all clinical anti-AR agents act by direct binding to the AR's hormone binding site. These drugs are therefore vulnerable to mutations which frequently arise at this region. Further, as they are structurally related they cannot be used in combination. There is therefore an unmet need for new therapeutics that inhibit the AR. By combining computer modeling, biological screening and structural biology, we have developed an entirely new class of anti-AR drugs that target a novel region of the AR (called BF3). Our lead compound efficiently inhibits the AR and shows efficacy in both PCa cell lines and xenograft animal models. Building off these proof-of-principle studies, this project will progress our lead compound to advanced preclinical development in preparation for clinical trials. The high incidence of PCa coupled with a relatively long disease course and the demographics of aging Canadian· population, will eventually make treatment of this cancer one of the largest expenditures in the health care budget. We anticipate that these new anti-AR drugs will replace or supplement existing anti-AR therapeutics and will provide new options for treating patients with late-stage PCa. Since the emergence of resistance is the lethal end-stage of the disease, we anticipate that the proposed research will eventually have a substantial impact on patient survival.