Grant: CIHR Fellowship

Prostate cancer is a leading cause of cancer related death in men. Although often curable when diagnosed early, tumours that become recurrent or metastatic are difficult to manage. Prostate tumour growth is driven by androgens, hormones that are produced by the body such as di-hydro-testosterone (DHT). Accordingly, treatment for patients involves reducing DHT production or blocking the specific interaction of this hormone with a protein residing within prostate cells called the androgen receptor (AR). These treatments are temporary, however, and the tumour cells invariably change at the genetic level into a "castration resistant" form, allowing growth even in the absence of DHT. Substantial progress has been made in understanding how androgens act at the molecular level. Within prostate cancer cells, the DHT molecule binds to the AR protein, "activating" the AR then causing the production of other cellular factors that promote tumour growth. For the activated receptor to exert its function, two AR proteins must form an assembly, a molecular process known as "dimerization". Thus, a treatment that specifically interferes with AR dimerization could prevent AR activation and possibly work in castration resistant cancer cells that are androgen independent. The research group at the Prostate Centre has successfully screened for compounds (i.e. drugs) that can block the interaction between the AR and DHT in living cells. This progress will be extended to screen for drugs that interfere with AR dimerization. Initially, biochemistry methods will be used to detect AR assemblies and gauge the effect of drugs on purified AR in solution (in vitro). Promising compounds will be tested in cultured prostate cancer cells and eventually in mice (in vivo). Targeting AR dimerization, rather than DHT binding, could potentially suppress tumour growth in even castration resistant patients, and would be a significant breakthrough in treatment of prostate cancer.