The role of fatty acid synthase in CRC

Fatty Acid Synthase (FASN), a key enzyme of de novo lipid synthesis, is significantly upregulated in colorectal cancer (CRC) and its activity is associated with worse prognosis. Our preliminary studies suggest that upregulation of FASN provides a survival advantage to cancer cells by reprogramming metabolic pathways including fatty acid (FA) oxidation and storage of de novo synthesized lipids. Therefore, the central hypothesis is that upregulation of FASN expression and activity significantly contributes to progression of CRC by altering metabolic and oncogenic pathways that promote survival of cancer cells. We will test the hypothesis through completion of the following aims: SPECIFIC AIMS: Aim 1 will elucidate the role of FASN in survival of CRC cells via regulation of FA oxidation and storage. Aim 2 will determine the effect of FASN inhibition on tumor growth and metabolism in patient-derived xenograft (PDX) models. STUDY DESIGN: We will utilize biological samples from patients, human primary cells and PDX models, which are the most advanced models for pre-clinical target and drug evaluations. These models will be used in conjunction with state-of-the-art approaches, including Stable Isotope-Resolved Metabolomics (SIRM) to evaluate the effect of FASN overexpression on cancer metabolism. CANCER RELEVANCE: CRC is the second most common cause of cancer death in men and women combined in the U.S. and in Kentucky. Despite advances in our understanding of the molecular basis of CRC and the increasing number of targeted therapies, treatment of advanced CRC frequently remains disappointing. New approaches to treat advanced CRC are urgently needed.