Molecular Mechanisms by which Statins Prevent and Reverse Hepatocellular Carcinoma

项目摘要/摘要 肝细胞癌是世界范围内癌症相关死亡的主要原因。HMG-CoA 还原酶(HMGCR)抑制剂他汀类药物在预防和治疗癌症方面显示出很高的潜力，包括 肝细胞癌。我们将研究他汀类药物抗肝癌的机制，并发现生物标志物以 预测治疗效果。通过我们之前发表的工作，我们使用了我们的条件转基因 他汀类药物抑制MYC信号执行抗癌的新途径 属性。此外，我们还发现MYC改变代谢途径以促进脂肪酸的合成。 葡萄糖和谷氨酰胺途径。TOFA抑制脂肪酸合成引起MYC显著消退 其疗效与MYC水平相关。他汀类药物(如阿托伐他汀)阻断心肌细胞MYC磷酸化 我们的MYC驱动的肝癌模型和抑制肿瘤的启动和进展(见我们的初步结果)。我们 假设MYC通路被他汀类药物抑制，这是他汀类药物可以防止 并通过直接的抗癌基因作用和恢复免疫监视来治疗肝癌。我们会 确定他汀类药物预防肝癌的机制，我们建议1)评估其抗癌作用 他汀类药物在MYC诱导肝癌不同进展阶段(MYC诱导前、MYC早期)的疗效 肿瘤发生、晚期肝细胞癌)和与NASH相关的情况；2)确定特定的代谢 他汀类药物在MYC-HCC中的调控途径；3)确定免疫系统和特异性的变化 他汀类药物对效应分子/细胞因子的影响；4)发现可预测他汀类药物疗效的生物标志物 在预防肝细胞癌方面。我们的团队包括医学肿瘤学、MYC癌基因和肿瘤方面的专业知识 免疫学(Felsher)、胃肠病与肝细胞癌(Dhanasekaran)和肝病与肝病(Verna 和布朗)。Verna博士和Brown博士是肝硬变网络(LCN)临床计划(RAF- CA-23-023)，目前正在研究降脂药物(他汀类药物)对高血压患者的影响 代偿性NASH、ALD、胆汁淤积性和隐源性肝硬变。LCN研究为我们提供了一个独特的 有机会通过使用我们的临床前转基因肝癌小鼠模型来确定机制，该模型可以 使用人类临床样本进行评估，以通过LCN提供给我们。我们的工作将有助于确定导致 他汀类药物阻断肝细胞癌的机制及其生物标志物的鉴定 预测何时这些药物在预防肝细胞癌方面最有用。

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.