Fatty Acid Synthase in Regulation of UDP-GlcNAc Synthesis in Colorectal Cancer

Colorectal cancer is the second leading cause of cancer-related deaths in the United States. Abnormal lipid synthesis and accumulation of certain lipids have a positive correlation with tumor growth and metastatic features of colorectal cancer, suggesting that an increase in lipid metabolism may be a causal factor of colorectal cancer. Thus, targeting lipid metabolism may provide a promising breakthrough therapy to specifically impair colorectal cancer growth and metastasis. The goal of research in my laboratory is to understand how lipid metabolism contributes to colorectal cancer and further develop lipid metabolism as a therapeutic target for this disease. Colorectal cancer cells speed up lipid metabolism either by increasing fatty acid synthesis inside cells or by enhancing uptake of dietary fatty acids. Fatty Acid Synthase (FASN) is a key enzyme of lipid synthesis. We found that elevated expression of FASN is associated with advanced stages of colorectal cancer and colorectal cancer metastasis in patients. We have also shown that inhibition of this enzyme significantly reduces formation of blood vessels which support tumor growth and lung and liver metastases in mice, suggesting that activation of this enzyme is a key mechanism promoting progression of colorectal cancer and metastasis. In collaboration with Sagimet Biosciences, the pharmaceutical company which has developed a first-in-class inhibitor of FASN, we demonstrated the anti-tumor activity of TVB-3664 in primary colorectal cancer cells and patient-derived xenografts (the tissue from a patient’s tumor is grown in a mouse). We are currently testing this novel FASN inhibitor in a clinical trial at Markey Cancer Center. To further advance our studies, we have developed unique mouse models with homozygous (complete) and heterozygous (50 percent) deletion of FASN in intestine and colon. Our preliminary studies show that FASN deletion significantly decreases the number of tumors formed and increases animal survival. Consistently, pharmacological inhibition of FASN, using the novel FASN inhibitor TVB-3664 in mice which spontaneously develop tumors, normalizes animal weight, when they kept on high fat diet, decreases number of tumors, and significantly increases animal survival. All these findings further support our hypothesis that FASN can be an effective therapeutic target for colorectal cancer. Recently, we have identified several novel mechanisms of resistance to novel FASN inhibitors including an increase in uptake of fatty acids from diet and utilization of alternative metabolic pathways inside of a cancer cell to compensate for FASN inhibition. We are investigating these mechanisms in order to design an effective combinational strategy to target lipid metabolism in cancer. Finally, my laboratory utilizes multiple models including patient-derived xenografts, colorectal cancer cell lines, organoid cultures (tumor cells cultured as 3D clusters) from cancer patients, and genetically modified models to perform metabolic analyses to delineate how metabolic characteristics of colorectal cancers define their susceptibility to FASN inhibition and improve patient selection and personalized medicine approaches