Project 2 is focused on an exciting clinical concept. PCa universally develops resistance to androgen-deprivation therapy (ADT), leading to metastatic CRPC. This is most frequently associated with reactivation of signaling through AR, the major driver of lethal CRPC and resistance to abiraterone and/or enzalutamide. This project uses novel and nonconventional approaches to inhibit AR signaling, regardless of the reactivation mechanism (mutation, amplification, ligand-independent splice variant expression), leveraging metabolic rewiring of lipid metabolism, a hallmark of PCa. Fatty Acid Synthase (FASN), the rate-limiting enzyme in de novo lipogenesis, is overexpressed in CRPC. FASN regulates AR expression, and preclinical data show FASN inhibition in PCa leads to reduced cell growth in vitro and in vivo and down-regulation of both full-length AR and its splice variants. Based on these findings, Project 2 will execute a clinical trial to test a clinical grade FASN inhibitor (TVB-2640) to sensitize cells to AR antagonists (Enzalutamide) in advanced, therapy resistant PCa, and define mechanisms and predictors of response.

Aim 1. To characterize the role of de novo lipogenesis in AR signaling pathway.

Aim 2. To perform a Phase-I dose-finding study of the FASN inhibitor TVB-2640 (Sagimet) in combination with Enzalutamide in men with mCRPC previously treated with ADT and Abiraterone