Molecular Transitions Driving AR Loss in Double Negative Prostate Cancer

PROJECT SUMMARY/ABSTRACT – PROJECT 2 Despite newer and more effective therapies, prostate cancer remains a leading cause of cancer-related deaths among men in the United States. There is a need to better subclassify prostate cancer, particularly tumors that develop resistance to androgen deprivation, to characterize and target resistance mechanisms, and to prioritize treatments for individual patients. Double-negative prostate cancer (DNPC) is an increasingly recognized and clinically important form of castration-resistant prostate cancer (CRPC) that lacks both androgen receptor and neuroendocrine marker expression. Recent studies from our group indicate that DNPC is linked to worse clinical outcomes compared to other CRPC molecular subtypes. Additionally, diagnosing DNPC is challenging due to the absence of reliable biomarkers, causing delays in diagnosis and missed opportunities for timely treatment. Thus, there is an urgent need for innovative methods to detect and track the progression of DNPC. Moreover, it is crucial to delineate vulnerabilities of DNPC to develop effective therapies for this aggressive CRPC subtype. In this proposal, we will test the central hypothesis that DNPC is a distinct molecular subtype of CRPC that exhibits targetable vulnerabilities through the following specific aims: Aim 1: Assess patient-level, cell- autonomous, and tumor microenvironmental determinants of DNPC. Aim 2: Define the lineage determinants and vulnerabilities of AR-null prostate cancers. Aim 3: Develop approaches to detect DNPC phenotypes in patients receiving AR-directed therapy. The completion of these studies will enhance our understanding of DNPC, lead to the development of biomarkers for DNPC detection, and identify novel targeted therapies for DNPC.