Project Summary/Abstract Prostate cancer (PCa) is the second most incident cancer in men worldwide and despite vast amounts of research, treatment of this disease remains elusive. The prostate is regulated by male hormones (e.g. testosterone) that activate the androgen receptor (AR) to trigger signaling pathways involved in the organ’s development and growth. In PCa, these hormones exert an important role in the onset and progression of the disease, and therefore have been the main therapeutic target for PCa patients. However, virtually all patients relapse and develop Castration-Resistant PCa (CRPC), the lethal stage of the disease. Therefore novel and more efficacious therapeutics are extremely important for PCa patients. In the F99-phase of this project, the potential of sphingolipid-based therapeutics for PCa will be examined. Ceramide nanoliposomes (CNL) are extremely efficacious in causing cell death of aggressive in vitro models of PCa, and these liposomes have a therapeutic potential also when combined with FDA-approved drugs that target the AR signaling axis. The working hypothesis is that AR regulates sphingolipid metabolism hindering the efficacy of CNL in PCa. To investigate the relationship between the androgen receptor and ceramide metabolism, we will specifically study (1) the mechanism’s by which AR regulates ceramide metabolism and how this impacts the efficacy of conventional therapeutics in PCa cells and (2) the efficacy of novel therapeutics in preclinical models of PCa to assess the translational potential of ceramide-based therapeutics for PCa. The novelty of the proposed work will result in delineating novel lipid-centric molecular mechanisms in prostate cancer that can impact novel therapeutics for patients with no current viable options. In the K00 component of this proposal, the impact of epigenetic marks in the regulation of lipid metabolism in tumors will be determined. I will also determine how manipulating lipid metabolism impacts the epigenome in cancer cells. Moreover, understanding the regulation between epigenetics and lipid biology in tumors will allow for target identification and recognition of the key pathways regulating these crucial machineries in cancer.