Molecular Mechanisms by which Statins Prevent and Reverse Hepatocellular Carcinoma

项目总结/摘要 肝细胞癌（HCC）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 HCC。我们将研究他汀类药物对抗HCC的机制，并发现生物标志物， 预测治疗效果。通过我们先前发表的工作，我们使用了我们的条件转基因技术， 小鼠HCC模型，以确定他汀类药物抑制MYC信号传导以执行抗癌的新途径。 特性.此外，我们发现MYC重新连接代谢途径，以促进脂肪酸的合成， 葡萄糖和谷氨酰胺途径。TOFA对脂肪酸合成的抑制导致MYC的显著消退 驱动的肿瘤，并且功效与MYC水平相关。他汀类（例如，阿托伐他汀）阻断MYC磷酸化， 我们的MYC驱动的HCC模型，并抑制肿瘤的发生和进展（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预防的一种机制。 并通过直接的抑癌基因作用以及恢复免疫监视来治疗HCC。我们将 为了确定他汀类药物预防HCC的机制，我们建议：1）评估他汀类药物的抗癌作用， 他汀类药物在MYC驱动的HCC的不同进展阶段（MYC诱导前， 肿瘤发生、晚期HCC）和与NASH相关的条件; 2）鉴定特异性代谢 MYC-HCC中他汀类药物调节的途径; 3）确定免疫系统和特异性 他汀类药物影响的效应物/细胞因子; 4）发现可预测他汀类药物疗效的生物标志物 预防HCC。我们的团队包括医学肿瘤学、MYC癌基因和肿瘤 免疫学（Felsher）、胃肠病学和HCC（Dhanasekaran）以及肝病学和肝病（Verna 布朗）。Verna博士和Brown博士是肝硬化网络（LCN）临床项目（RAF- CA-23-023），目前正在研究降脂药物（他汀类药物）在患有 代偿性NASH、ALD、胆汁淤积性和隐源性肝硬化。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肝癌转基因小鼠模型来确定机制， 使用人类临床样本进行评估，通过LCN提供给我们。我们的工作将有助于确定 确定他汀类药物阻断HCC的机制，以及确定可以 预测这些药物何时最有可能用于预防HCC。

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.