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Simple Summary: Prostate cancer therapy suffers from a lack of effective targets because, typically, success with blockade of the androgen receptor gives way to drug resistance and lethal disease relapse. Large scale genome sequencing efforts have demonstrated that lethal recurrent disease most often presents with loss of the PTEN and TP53 tumor suppressors. Unfortunately, the systematic testing of PTEN/ PI 3-Kinase pathway-specific inhibitors has shown only limited results in prostate cancer trials. Thus, there are currently no FDA-approved drugs targeting this axis in prostate cancer patients. Here we propose a new target, the FABP5 lipid carrier. FABP5 amplification and surge in expression are strongly correlated to that of the MYC oncogene, a known driver of advanced PTEN-deficient prostate cancer. Here, we present a new pre-clinical platform to assess the efficacy and biology of inhibiting FABP5 with small molecules. Our platform is based on a PTEN-deficient prostate cancer cell type that is insensitive to standard of care therapies. Resistance to standard of care taxane and androgen deprivation therapy (ADT) causes the vast majority of prostate cancer (PC) deaths worldwide. We have developed RapidCaP, an autochthonous genetically engineered mouse model of PC. It is driven by the loss of PTEN and p53, the most common driver events in PC patients with life-threatening diseases. As in human ADT, surgical castration of RapidCaP animals invariably results in disease relapse and death from the metastatic disease burden. Fatty Acid Binding Proteins (FABPs) are a large family of signaling lipid carriers. They have been suggested as drivers of multiple cancer types. Here we combine analysis of primary cancer cells from RapidCaP (RCaP cells) with large-scale patient datasets to show that among the 10 FABP paralogs, FABP5 is the PC-relevant target. Next, we show that RCaP cells are uniquely insensitive to both ADT and taxane treatment compared to a panel of human PC cell lines. Yet, they share an exquisite sensitivity to the small-molecule FABP5 inhibitor SBFI-103. We show that SBFI-103 is well tolerated and can strongly eliminate RCaP tumor cells in vivo. This provides a pre-clinical platform to fight incurable PC and suggests an important role for FABP5 in PTEN-deficient PC. [ABSTRACT FROM AUTHOR]