Grant: Project Grant

Prostate cancer continues to be a leading cause of death for men in North America The main factor that drives the transformation that changes normal prostate tissue into cancerous lesions is the androgen receptor (AR), a molecular signalling protein, which is induced by male sex steroid hormones, such testosterone, to interact with DNA in the cell nucleus, thereby stimulating tumor growth. Conventional treatment, which seeks to block the AR interaction with hormones, inevitably fails due to the mutating genetic landscape within tumors that alter AR proteins permit them to evade drug-inhibition and to continue sending the growth signal. The development of small molecules that attack the molecular functions of the androgen receptor, distinct from steroid recruitment, is hence a novel area of investigation to evade resistance to conventional treatments. Our laboratory has already created drug prototypes that compromise the necessary DNA interacting function of the protein, resulting in a historic drug-development partnership between the University of British Columbia and Roche Pharmaceuticals. Now, this strategy will be applied to develop small molecules that target another essential function of the androgen receptor, a process known as dimerization, whereby two AR proteins interact with each other to facilitate activation in the cell nucleus. An "anti-dimer" compound would clearly be useful to treat such resistant forms of prostate cancer where only months of survival benefit are offered through using conventional agents. Thus, our pioneering work has the potential to inform the next model of prostate cancer treatment with novel alternative anti-cancer molecules.