Project Summary/Abstract Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide. HMG-CoA reductase (HMGCR) inhibitors, statins, show high potential in the prevention and treatment of cancer including HCC. We will investigate the mechanism by which statins fight against HCC and discovering the biomarkers to predict the therapeutic effects. Through our previously published work, we have used our conditional transgenic mouse models of HCC to identify a novel pathway that statins suppress MYC signaling to execute the anti-cancer properties. Also, we identified that MYC rewires metabolic pathways to promote fatty acid synthesis in addition to glucose and glutamine pathways. Inhibition of fatty acid synthesis by TOFA elicits dramatic regression of MYC driven tumors and the efficacy correlates to MYC level. Statin (e.g., Atorvastatin) blocks MYC phosphorylation in our MYC-driven HCC model and inhibit tumor initiation and progression (see our Preliminary Results). We hypothesize that the MYC pathway is suppressed by statins and this is a mechanism by which statins can prevent and treat HCC, both through direct anti-oncogene effects as well as by restoring immune surveillance. We will determine the mechanisms by which statins protect against HCC, we propose to 1) evaluate the anti-cancer efficacy of statins at different progression stages of MYC driven HCC (before MYC induction, early stage of tumorigenesis, late stage of HCC) and the condition of association with NASH; 2) identify specific metabolism pathways regulated by statin in MYC-HCC; 3) define the changes of immune system and specific effectors/cytokines influenced by statin; 4) discover the biomarkers that can predict the therapeutic effect of statin in prevention of HCC. Our team includes expertise in Medical Oncology, the MYC oncogene and Tumor Immunology (Felsher), Gastroenterology and HCC (Dhanasekaran) and Hepatology and liver disease (Verna and Brown). Dr. Verna and Dr. Brown are members of the Liver Cirrhosis Network (LCN) clinical program (RAF- CA-23-023) and are currently investigating the effect of lipid lowing medications (Statins) in patients with compensated NASH, ALD, cholestatic and cryptogenic cirrhosis. The LCN study provides us with a unique opportunity to identify mechanisms through use of our preclinical transgenic mouse model of HCC that can be evaluated using human clinical samples to available to us through the LCN. Our work will help identify lead to the identification of the mechanisms by which statins can block HCC as well as identify biomarkers that can predict when these agents are most likely to be useful in preventing HCC.