Chemoprevention of HCC related to MAFLD

代谢(功能障碍)相关性脂肪性肝病(MAFLD)现在是 美国的肝细胞癌。目前，没有针对肝脏特异的治疗方法被批准用于患有以下疾病的个人 太棒了。可能阻止肝癌发生的疗法--即化学预防--是唯一可行的解决办法 以遏制与MAFLD相关的肝癌的上升趋势。在此背景下，三类药物(他汀类、二甲双胍、 和格列酮)有很大的希望，因为它们作用于不同的新陈代谢和/或应激反应 在MAFLD相关的肝癌发生中很重要的通路，通常用于治疗代谢紊乱， 而且随处可见。据我们所知，还没有研究在MAFLD中检测肝细胞癌的化学预防。的确有 关于这些药物的潜在危害，特别是与肝脏相关的不良事件(AEs)的信息也有限 这在MAFLD患者中可能很常见。化学预防的好处和坏处可能是不同的 在不同的亚群中。我们的研究将评估肝细胞癌化学预防的益处和危害 MAFLD患者的三种有前景的治疗方法。为此，我们将使用、扩展和扩展 先前集合的、特征良好的全国MAFLD患者队列具有广泛的纵向临床， 药房和实验室数据链接到癌症登记、死亡登记和临床医生的详细信息 笔记。使用这个队列，作为初步工作的一部分，我们显示了MAFLD和MAFLD之间的强烈关联 并报道了代谢特征对肝癌风险的相加效应。目标1(受益于 化学预防)，我们将进行一系列精心设计的研究来评估化学预防 他汀类药物(与非他汀类药物相比)、二甲双胍(与非他汀类药物相比)和吡格列酮(与非他汀类药物相比)对血管紧张素转换酶活性的影响 降低发生肝细胞癌的风险。我们还将评估化学预防效果的异质性，特别是 重点关注伴有和不伴有肝硬变的MAFLD患者，具有不同程度共存代谢特征的患者， 并进行剂量-持续时间分析，以指导量身定制的化学预防。对于目标2(危害 化学预防)，我们将使用机器学习中的创新，然后手动审查病历 对纳入的患者中潜在的与药物有关的不良反应进行全面的比较评估 目标1：模拟试验。研究表明，遗传因素导致了癌症反应的差异。 化学预防。在目标3(益处的遗传决定因素)中，我们将使用正在进行的前瞻性研究的数据 MAFLD-肝硬变患者队列检查几个可疑的遗传标记可能会改变 二甲双胍和/或他汀类药物对MAFLD-肝硬变患者的化学预防作用我们的研究是 意义重大，因为它将为指导方针，谁，何时和如何建议化学预防 MAFLD患者。除了阐明在普通MAFLD人群中潜在的化学预防作用外， 我们对个性化化学预防的强调是新颖的。

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.