Fatty Acid Synthesis and Prostate Cancer: Hormonal Regulation and Anti-Metabolite Targeting of an Acquired Function in Neoplasia

Fatty acid synthase FAS performs the anabolic conversion of dietary carbohydrate or protein to fat. FAS expression is low in most normal tissues, but is elevated in many human cancers, including androgen sensitive and androgen independent prostate cancer. This project seeks to characterize androgen mediated and androgen independent mechanisms for fatty acid synthesis pathway activation during prostate cancer progression, using cell culture and animal models of prostate cancer, and analyzing human tumor tissue in parallel. It further seeks to evaluate the potential therapeutic utility of FAS inhibitors for prostate cancer in preclinical models. Progress in the first year includes development and validation of cell culture and xenograft model systems for FAS expression and activity, and evaluation of FAS inhibitor efficacy in vitro and in three tumor xenograft models. Metabolic labeling studies of human prostate carcinoma tissues have confirmed functional activation of the fatty acid synthetic pathway in clinical disease. The data suggest that FA synthesis provides an important functional aspect of the malignant phenotype in prostate cancer, perhaps supporting cell growth or survival. FAS expression is upregulated by alternate signaling pathways important for prostate cancer growth under androgen withdrawal, suggesting that FAS may serve as a novel target for anti-metabolite therapy in prostate cancer.