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.

项目摘要/摘要 肝细胞癌（HCC）是全球与癌症相关死亡率的主要原因。 HMG-COA 还原酶（HMGCR）抑制剂，他汀类药物在预防和治疗癌症中表现出很高的潜力 HCC。我们将调查他汀类药物与HCC作战并发现生物标志物的机制 预测治疗作用。通过先前发表的工作，我们使用了条件转基因 HCC的鼠标模型以识别汀类药物抑制MYC信号以执行抗癌的新途径 特性。另外，我们确定MYC还会重新促进代谢途径，以促进脂肪酸合成。 葡萄糖和谷氨酰胺途径。通过豆腐抑制脂肪酸合成引起MYC的急剧回归 驱动的肿瘤和功效与MYC水平相关。他汀类药物（例如atorvastatin）阻止MYC磷酸化 我们的MYC驱动的HCC模型并抑制肿瘤的启动和进展（请参阅我们的初步结果）。我们 假设MYC途径被他汀类药物抑制，这是他汀类药物可以防止的机制 并通过直接抗癌基因效应以及恢复免疫监测来治疗HCC。我们将 确定他汀类药物免受HCC的保护的机制，我们建议1）评估抗癌者 他汀类药物在MYC驱动的HCC的不同进展阶段的功效（MYC归纳之前，早期的早期阶段 肿瘤发生，HCC后期）和与NASH的关联状况； 2）确定特定的新陈代谢 MYC-HCC中他汀类药物调节的途径； 3）定义免疫系统的变化和特定的变化 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作用的生物标志物 预防HCC。我们的团队包括医学肿瘤学，MYC癌基因和肿瘤方面的专业知识 免疫学（Felsher），胃肠病学和HCC（DHANASEKARAN）和肝病（Verna） 和棕色）。 Verna博士和Brown博士是肝硬化网络（LCN）临床计划的成员（RAF- CA-23-023），目前正在研究脂质降低药物（他汀类药物）的影响 补偿的纳什，ALD，胆汁淤积和隐形肝硬化。 LCN研究为我们提供了独特的 通过使用我们可以使用的临床前转基因小鼠模型来识别机制的机会 使用人类临床样本通过LCN进行评估。我们的工作将有助于确定导致 他汀类药物可以阻止HCC的机制的识别以及可以识别可以识别的生物标志物 预测这些药物何时最有可能在预防HCC中有用。