Molecular Mechanisms by which Statins Prevent and Reverse Hepatocellular Carcinoma

他汀类药物预防和逆转肝细胞癌的分子机制

• 批准号: 10856787
• 负责人: DEAN W FELSHER
• 金额: $ 34.19万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-19 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10856787
• 关键词: Biological Markers; Blood; Cancer Etiology; Cellular Metabolic Process; Cholestasis; Cholesterol; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Cohort Studies; Collaborations; Compensation; Cryptogenic cirrhosis; Cytometry; Diagnostic; Etiology; Fatty Acids; Fibrosis; Gastroenterology; Glucose; Glutamine; Hepatic; Hepatology; Homeostasis; Human; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immune; Immune system; Immunologic Markers; Immunologic Surveillance; Inflammation; Knowledge; Laboratories; Lead; Letters; Libraries; Lipids; Liver Cirrhosis; Liver diseases; MYC gene; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Medical Oncology; Meta-Analysis; Metabolic; Metabolic Pathway; Metabolism; Modeling; Molecular; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Oncology; Oxidative Stress; Oxidoreductase; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphorylation; Prevention; Preventive; Preventive therapy; Primary carcinoma of the liver cells; Proliferating; Property; Publishing; Reporting; Research; Research Personnel; Risk; Risk Reduction; Sampling; Series; Signal Transduction; System; Tetanus Helper Peptide; Therapeutic Effect; Transgenic Mice; Transgenic Model; Transgenic Organisms; Travel; Tumor Suppressor Genes; United States National Institutes of Health; Work; anti-cancer; anticancer research; atorvastatin; biomarker identification; cancer therapy; carcinogenesis; cytokine; epidemiology study; fighting; imaging agent; improved; inhibitor; insight; ionization; lipid biosynthesis; liver cancer model; mass spectrometric imaging; member; metabolomics; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; novel therapeutics; patient derived xenograft model; pre-clinical; prevent; programs; prospective; rosuvastatin; single-cell RNA sequencing; tumor; tumor immunology; tumor initiation; tumor progression; tumorigenesis

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.

项目概要/摘要 肝细胞癌（HCC）是全球癌症相关死亡的主要原因。 HMG辅酶A 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巨大潜力，包括 肝癌。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。通过我们之前发表的工作，我们使用了我们的有条件转基因 HCC 小鼠模型确定他汀类药物抑制 MYC 信号传导以执行抗癌作用的新途径 特性。此外，我们还发现 MYC 重新连接代谢途径以促进脂肪酸合成 葡萄糖和谷氨酰胺途径。 TOFA 抑制脂肪酸合成可引起 MYC 急剧消退 驱动肿瘤，疗效与 MYC 水平相关。他汀类药物（例如阿托伐他汀）可阻断 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（参见我们的初步结果）。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 通过直接抗癌基因作用以及恢复免疫监视来治疗肝癌。我们将 为了确定他汀类药物预防 HCC 的机制，我们建议 1) 评估其抗癌作用 他汀类药物在 MYC 驱动的 HCC 不同进展阶段（MYC 诱导前、早期阶段）的疗效 肿瘤发生、HCC 晚期）以及与 NASH 相关的状况； 2）确定特定的代谢 MYC-HCC 中他汀类药物调节的途径； 3）定义免疫系统的变化和具体 受他汀类药物影响的效应子/细胞因子； 4）发现可以预测他汀类药物治疗效果的生物标志物 预防肝癌。我们的团队拥有肿瘤内科、MYC 癌基因和肿瘤方面的专业知识 免疫学 (Felsher)、胃肠病学和 HCC (Dhanasekaran) 以及肝病学和肝病 (Verna) 和布朗）。 Verna 博士和 Brown 博士是肝硬化网络 (LCN) 临床计划 (RAF- CA-23-023），目前正在研究降脂药物（他汀类药物）对患有以下疾病的患者的影响： 代偿性 NASH、ALD、胆汁淤积性和隐源性肝硬化。 LCN 研究为我们提供了独特的 通过使用我们的临床前转基因小鼠 HCC 模型来确定机制的机会 使用人类临床样本进行评估，并通过 LCN 向我们提供。我们的工作将有助于确定导致 鉴定他汀类药物阻断 HCC 的机制以及鉴定可预防 HCC 的生物标志物 预测这些药物何时最有可能有助于预防 HCC。