Grant: Project Grant

Targeting the androgen receptor (AR) has been the cornerstone of treatment for men suffering from prostate cancer, essentially starving tumors of the fuel they need to grow and survive. However, these therapies have been a double-edged sword; undoubtedly they have benefited survival, but in nearly 25% of patients the tumors eventually come back even stronger and more aggressive than before. For these men who progress to this deadly form of prostate cancer called Neuroendocrine Prostate Cancer (NEPC), the only treatment option is a highly toxic chemotherapy however the survival is only measured in months. Our research is focused on deciphering how prostate tumors treated with AR-directed therapy evolve into NEPC. Toward this end, we discovered a protein called BRN2 that is essential for the growth and survival of NEPC. Moreover, we have developed drugs that can inhibit BRN2 and display potential to inhibit NEPC progression. The current proposal outlines the following strategies: • Understand BRN2's role in structural changes in the genome and how that causes treatment resistance as well as this transformation to NEPC. • Test our first-in-field BRN2 inhibitors on human patient derived NEPC tumors that are grown in mice. • Test the efficacy of the BRN2 inhibitors in combination with current AR inhibitors. Measure effects on tumor growth as well as transformation to NEPC.