Grant: Project Grant

Prostate tumours are addicted to the androgen receptor (AR) for 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, nearly 25% 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 pro-neural 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 the role of ASCL1 in altering the structure of DNA and its impact on treatment resistance and the transformation to NEPC. 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 prostate cancer.