Chemoprevention of HCC related to MAFLD

与 MAFLD 相关的 HCC 的化学预防

• 批准号: 10410751
• 负责人: FASIHA KANWAL
• 金额: $ 21.22万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10410751
• 关键词: Address; Adverse event; Affect; Age; American; Cancer Etiology; Cessation of life; Chemoprevention; Chemopreventive Agent; Child; Cirrhosis; Clinical; Clinical Trials; Cohort Studies; Complement; Data; Diabetes Mellitus; Dose; Dyslipidemias; Etiology; Evaluation; Fibrosis; Foundations; General Population; Genes; Genetic; Genetic Determinism; Genetic Markers; Goals; Guidelines; Hepatocarcinogenesis; Heterogeneity; High Prevalence; Hospitals; Hybrids; Individual; Knowledge; Laboratories; Link; Lipids; Liver; Liver Cirrhosis; Liver diseases; Machine Learning; Malignant neoplasm of liver; Manuals; Measures; Medical; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolic syndrome; Metformin; Natural Language Processing; Non obese; Obesity; Outcome; Pathogenesis; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Pharmacoepidemiology; Pharmacology; Pharmacy facility; Phenotype; Pioglitazone; Population; Prevention; Primary carcinoma of the liver cells; Prospective cohort; Registries; Reporting; Research; Research Design; Retrospective cohort; Risk; Risk Factors; Series; Severities; Severity of illness; Subgroup; Thiazolidinediones; Toxic effect; United States Department of Veterans Affairs; Work; adverse event risk; base; biological adaptation to stress; burden of illness; cancer chemoprevention; cancer risk; carcinogenesis; chronic liver disease; clinical practice; cohort; comparative; curative treatments; design; diabetes control; experimental study; fatty liver disease; high risk; high risk population; innovation; metabolic-associated fatty liver disease; mortality; neoplasm registry; novel; predicting response; prevent; programs; response; stem; trait; tumor

Metabolic (dysfunction) associated fatty liver disease (MAFLD) is now one of the most important risk factors for hepatocellular cancer (HCC) in the U.S. Currently, no liver-specific therapies are approved for individuals with MAFLD. Therapy that may block hepatocarcinogenesis – i.e., chemoprevention – is the only practical solution to stem the rising tide of MAFLD-related HCC. In this context, three classes of medications (statins, metformin, and glitazones) hold substantial promise because they act on different metabolic and/or stress-response pathways important in MAFLD-related hepatocarcinogenesis, are commonly used to treat metabolic disorders, and widely available. To our knowledge, no study has examined HCC chemoprevention in MAFLD. There is also limited information about potential harms of these drugs, especially liver related adverse events (AEs) which may be common in persons with MAFLD. The benefits and harms of chemoprevention are likely different in different subgroups. Our study will evaluate the benefits and harms of HCC chemoprevention with these three promising therapies in individuals with MAFLD. To do so, we will use, expand and extend a previously assembled, well-characterized national cohort of MAFLD patients with extensive longitudinal clinical, pharmacy, and laboratory data linked to detailed information from cancer registry, death registry and clinician notes. Using this cohort, and as part of preliminary work, we showed a strong association between MAFLD and HCC and reported an additive effect of metabolic traits on HCC risk. For Aim 1 (benefits of chemoprevention), we will perform a series of carefully designed studies to evaluate the chemopreventive effects of statins (vs. no statins), metformin (vs. no metformin) and pioglitazone (vs. no pioglitazone) in reducing risk of incident HCC. We will also assess the heterogeneity of chemopreventive effects, with specific focus on MAFLD patients with and without cirrhosis, those with varying severity of co-existing metabolic traits, and perform dose-duration analyses to guide tailored chemoprevention. For Aim 2 (harms of chemoprevention), we will use innovations in machine learning followed by manual review of medical charts to conduct a comprehensive comparative evaluation of potential drug-related AEs among patients included in Aim 1 emulated trials. Studies show that genetic factors contribute to differences in response to cancer chemoprevention. In Aim 3 (genetic determinants of benefits), we will use data from an ongoing prospective cohort of patients with MAFLD-cirrhosis to examine few suspected genetic markers that may modify the chemopreventive effects of metformin and/or statins in individuals with MAFLD-cirrhosis. Our research is significant because it will inform guidelines about who, when and how to recommend chemoprevention in patients with MAFLD. Besides elucidating a potential chemopreventive effect in the general MAFLD population, our emphasis on personalized chemoprevention is novel.

代谢（功能障碍）相关脂肪肝病（MAFLD）现在是最重要的风险因素之一 目前，美国肝细胞癌（HCC）（HCC）目前，尚无肝脏特异性疗法被批准 黑手党。可能阻止肝癌发生的治疗（即化学预防）是唯一的实用解决方案 阻止与MAFLD相关的HCC的上升潮流。在这种情况下，三类药物（他汀类药物，二甲双胍， 和Glitazones）具有实质性的希望，因为它们对不同的代谢和/或应力反应作用 与MAFLD相关的肝癌发生重要的途径，通常用于治疗代谢性疾病， 并广泛使用。据我们所知，尚无研究检查MAFLD中的HCC化学预防。有 同样有限有关这些药物潜在危害的信息，尤其是与肝脏相关的不良事件（AES） 这可能是与黑手党的人一样常见的。化学预防的好处和危害可能不同 在不同的亚组中。我们的研究将评估HCC化学预防的益处和危害 三个承诺在黑手党患者中进行疗法。为此，我们将使用，扩展和扩展 以前组装的，良好的国家人群的MAFLD患者具有广泛的纵向临床， 药房和实验室数据与癌症注册表，死亡注册表和临床的详细信息有关 笔记。使用此队列，作为初步工作的一部分，我们表现出MAFLD与 HCC并报告了代谢特征对HCC风险的额外影响。目标1（好处 化学预防），我们将进行一系列精心设计的研究，以评估化学预防 他汀类药物（毒素），二甲双胍（vs.无二甲双胍）和吡格列酮（vs.无吡格列酮）的影响 降低事件HCC的风险。我们还将评估化学预防作用的异质性，具体 专注于有和没有肝硬化的黑人群体患者，与共存代谢性状不同的患者， 并进行剂量持续分析以指导定制的化学预防。目标2（危害 化学预防），我们将在机器学习中使用创新，然后对医学图表进行手动审查 对包括在内的患者中的潜在药物相关AE进行全面的比较评估 AIM 1模拟试验。研究表明，遗传因素有助于对癌症的反应差异 化学预防。在AIM 3（遗传决定者的利益）中，我们将使用正在进行的潜在的数据 Mafld-Cirrhosis的患者队列可检查少数可疑的遗传标记，这些标志可能会改变 二甲双胍和/或他汀类药物对MAFLD-CIRRHOSIS的个体的化学预防作用。我们的研究是 意义重大，因为它将为指南提供有关谁，何时以及如何推荐化学预防的准则 MAFLD的患者。除了阐明在一般黑手党人群中的潜在化学预防作用外， 我们对个性化化学预防的强调是新颖的。