Grant: Project Grant

Prostate tumours are addicted to the androgen receptor (AR) for their growth and survival. Capitalizing on this inherent weakness, potent drugs have been developed to "turn off" the AR and starve cancer cells of fuel. These therapies are widely used in the clinic and have undoubtedly benefited patient survival; however, they are merely palliative and no patients are cured. Alarmingly, early 20% of patients progress to a highly aggressive and deadly form of prostate cancer, called neuroendocrine prostate cancer (NEPC), where treatment remains decades old toxic chemotherapy and survival is measured in months. Our research is focused on uncovering how prostate tumours evolve into NEPC following AR targeted therapy. We discovered that the transition to NEPC is orchestrated by ASCL1, a proneural protein that changes the structure of DNA to allow a prostate cancer cell to turn on neuronal genes and take on the identity of a neuroendocrine cell. In the current proposal, we aim to decipher how ASCL1 interacts with chromatin remodeling factors to support lineage conversion, treatment resistance and the transformation to NEPC and identify epigenetic dependency and used currently available drug to move our finding to the clinic. This work will advance our understanding of how prostate tumours evade therapy by transitioning to NEPC, and inform future therapeutic strategies to benefit patients with aggressive neuroendocrine prostate cancer with ASCL high tumors. This work directly addresses the overarching challenge to develop treatment to improve outcome of men with lethal prostate cancer and define the biology of lethal cancer in a segregated population to facilitate rapid translation of our finding to the clinic.