Conversion of prostate cancer from an anti-androgen responsive form to an androgen resistant one represents the most common form of therapeutic resistance of this cancer. This can occur through mutations that alter the androgen receptor protein such that it no longer needs ligand binding to be active, or in some cases even utilizes the inhibitor as an activator. Newer anti-androgens have been designed to minimize these resistance mechanisms, but drug resistance remains a challenge even for this agents. With the rise in use of newer androgen receptor inhibitors, a new form of resistance has emerged in which the original prostate adenocarcinoma changes cell fate to a neuroendocrine type of cancer that no longer expresses the androgen receptor and hence is treatment refractory. Transdifferentiation from an adenocarcinoma to a neuroendocrine tumour type is frequently accompanied by loss of the retinoblastoma gene (RB1). My research group has studied the RB1 gene, the effects of RB1mutation on cells, and its role as an epigenetic regulator of vast gene networks. In this proposal, we intend to elucidate mechanisms that RB1 uses to facilitate the inhibition of this lineage conversion to improve outcomes for prostate cancer patients.