Metabolism and prostate cancer

Genetic alterations in cancer define specific metabolic pathways that support their survival and growth. The central hypothesis driving research efforts in the Loda lab is that simultaneous targeting of rate limiting metabolic enzymes together with “driving” oncogenes that determine metabolic re-wiring, is cancer cell-specific and may result in synthetic lethality. In many papers over several years, we discovered significant interactions between body mass index, FASN genetic polymorphisms and high unsaturated fat diet with prostate cancer, suggesting that systemic alterations in lipid metabolism contribute to poor prostate cancer outcome. While exogenous lipids contribute to the pathogenesis of prostate cancer, maintenance and progression depend mainly on enhanced endogenous synthesis, centered on the highly upregulated rate limiting enzyme fatty acid synthase (FASN). We discovered that the de-ubiquitinating enzyme USP2a stabilizes FASN by preventing its degradation and formally demonstrated that FASN is a “metabolic oncogene” in prostate cancer. Investigating ties between cell cycle control and metabolism, we showed that endogenous synthesis of fatty acids is required at the G2/M transition and represents a novel “lipogenic checkpoint”. Inhibition of de novo lipogenesis by genetic or pharmacologic means in prostate cancer cells results in increase in reactive oxygen species due to peroxidation of polyunsaturated fatty acids taken up from the microenvironment to compensate endogenous inhibition. Importantly, downregulation of both the androgen receptor and its ligand-independent splice variants occurs as a result of FASN inhibition. Subsequently, cancer cells can undergo cell cycle arrest, apoptosis or ferroptosis. We reasoned that both the energy sensor AMPK, a master regulator of metabolism and lipogenesis, and FASN, the rate-limiting enzyme for de novo lipogenesis, represent ideal targets in prostate cancer. This may be therapeutically exploited with FASN inhibitors or AMPK activators. Inhibition of lipogenesis is actively being exploited therapeutically. We designed and recently opened a Phase I, FASN inhibitor (TVB-2640) Administered in Combination with Enzalutamide in Men with Metastatic Castration-Resistant Prostate Cancer (mCRPC). This is the first clinical trial to evaluate a new approach to treating metastatic, castration-resistant prostate cancer by targeting the AR pathway through inhibition of lipid synthesis. Enrollment began in August 2023 (ClinicalTrials.gov ID NCT05743621).