Trial of Statins for Chemoprevention in Hepatocellular Carcinoma

他汀类药物用于肝细胞癌化学预防的试验

• 批准号: 10297899
• 负责人: RAYMOND T CHUNG
• 金额: $ 67.59万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10297899
• 关键词: Adult; Adverse event; Affect; Biological Markers; Biopsy; Cancer Etiology; Cell Proliferation; Cessation of life; Chemoprevention; Chemopreventive Agent; Cirrhosis; Clinical; Clinical Chemoprevention; Clinical Trials; Companions; Complication; Conduct Clinical Trials; Data; Development; Disease Progression; Dose; Drug Kinetics; Etiology; Fibrosis; Future; Gene Expression; Hepatic; Hepatology; Human; Immunohistochemistry; Incidence; Inflammation; Infrastructure; International; Intervention; Length; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Measures; Meta-Analysis; Metabolic; Molecular; Monitor; Observational Study; Oncogenic; Outcome; Participant; Pathway interactions; Patient Selection; Patients; Pattern; Persons; Pharmacodynamics; Phase; Phase II Clinical Trials; Placebos; Positioning Attribute; Predisposing Factor; Prevention; Prevention trial; Primary carcinoma of the liver cells; Prognosis; Prognostic Marker; Public Health; Randomized; Randomized Clinical Trials; Randomized Controlled Trials; Reporting; Reproducibility; Research; Research Personnel; Research Project Grants; Resources; Risk; Risk Reduction; Safety; Sample Size; Serious Adverse Event; Serum; Signal Pathway; Signal Transduction; Surrogate Markers; Survival Rate; Testing; Therapeutic; Time; Tissue Sample; Translating; Translational Research; Viral; arm; atorvastatin; base; cancer cell; cancer chemoprevention; cancer risk; circulating biomarkers; clinical center; cohort; design; double-blind placebo controlled trial; efficacy testing; efficacy trial; epidemiologic data; follow-up; genetic signature; hazard; high risk; improved; in vivo; innovation; intrahepatic; lipophilicity; liver biopsy; liver transplantation; mortality; neoplastic; novel; novel strategies; patient population; pharmacodynamic biomarker; population based; pre-clinical; prevent; primary endpoint; prognostic; prospective; randomized controlled design; research clinical testing; risk prediction; screening; secondary endpoint; standard of care; trend; tumor; two-arm study

PROJECT SUMMARY Worldwide, hepatocellular carcinoma (HCC) represents the fifth most common cancer and the second-leading cause of cancer-related mortality. In the U.S., both the HCC incidence and mortality are increasing at an alarming pace. Despite these concerning trends, treatment options for HCC remain limited, and the prognosis is grim, with a 5-year survival rate of just 15%. Thus, identifying effective strategies to prevent the development of incident HCC represents a critical public health need. A growing body of preclinical and population-based observational data now demonstrate that lipophilic statins, and in particular atorvastatin, reduces hepatic inflammation, cellular proliferation and cancer cell invasion, and reduces the incidence of HCC, in part by acting on relevant pathways, including the Hippo-YAP signaling pathway. However, despite these promising data, well-designed randomized controlled trials (RCTs) of atorvastatin for HCC prevention have not yet been reported. Historically, the feasibility of an HCC prevention trial has been limited by large sample size and long lengths of follow-up required to assess target endpoints. Recently, however, our group has derived and validated a 186-gene expression Prognostic Liver Signature (PLS), that represents an accurate, reproducible and highly reliable surrogate biomarker for HCC risk in multiple international cohorts of all major viral and non-viral etiologies of cirrhosis. Further, we have demonstrated that therapeutic modulation of the PLS accurately recapitulates future risk of developing incident HCC tumors, both in vivo and in confirmatory human studies. Finally, we and others have demonstrated in human liver tissue samples that atorvastatin modulates the PLS in part by acting on the Hippo-YAP pathway. Thus, the PLS represents a novel and highly tractable surrogate biomarker endpoint for an RCT of atorvastatin for the reduction of incident HCC risk. In this proposal, we will conduct a phase II RCT in 60 patients with compensated cirrhosis, designed to test the efficacy, safety and tolerability of 48 weeks of atorvastatin for the reduction of HCC risk, defined by our validated PLS profile. All subjects will have a high-risk PLS defined at screening liver biopsy, and subjects will be randomly assigned to 1 of 2 study arms for the 48-week study period: atorvastatin 20mg/day or placebo, with appropriate monitoring for the 48-week period, followed by a repeat biopsy at week 48 to assess for improvement in the PLS profile. We will also confirm whether atorvastatin has adequately engaged its targets by evaluating pharmacokinetics/pharmacodynamics, pre/neoplastic markers, and alteration in the Hippo-YAP pathway. We hypothesize that PLS-based HCC risk level decreases in the atorvastatin arm at the end of 48-week treatment. If atorvastatin treatment is effective, safe and well-tolerated, it could become the first chemopreventive agent designed to prevent the development of HCC, guided by PLS, in the growing population of patients in the U.S. who are affected by cirrhosis and are at high risk for this devastating complication.

项目总结 在世界范围内，肝细胞癌是第五大常见癌症和第二大常见癌症 癌症相关死亡的原因。在美国，肝癌的发病率和死亡率都在以惊人的速度增长 佩斯。尽管有这些令人担忧的趋势，但肝癌的治疗选择仍然有限，预后严峻， 5年存活率仅为15%。因此，确定有效的战略来防止事件的发展 肝细胞癌代表着一个重要的公共卫生需求。越来越多的临床前和基于人群的观察 现在的数据表明，脂溶性他汀类药物，特别是阿托伐他汀，可以减少肝脏炎症，细胞 增殖和癌细胞侵袭，并降低肝癌的发病率，部分是通过作用于相关途径， 包括河马-YAP信号通路。然而，尽管有这些有希望的数据，精心设计的随机 阿托伐他汀预防肝癌的对照试验(RCT)尚未见报道。从历史上看，可行性 肝癌预防试验的有效性受到大样本量和评估所需的长时间随访的限制。 目标终端。然而，最近，我们的团队已经推导并验证了186个基因表达的预后 肝脏标志物(PLS)，代表了一种准确、可重复性和高度可靠的肝细胞癌替代生物标志物 肝硬变所有主要病毒性和非病毒性病因的多个国际队列的风险。此外，我们还拥有 证明了对偏最小二乘法的治疗调整准确地概括了未来发生事件的风险 肝细胞癌肿瘤，包括体内和验证性的人体研究。最后，我们和其他人在人类中展示了 阿托伐他汀部分通过作用于河马-YAP途径来调节偏最低密度脂蛋白的肝组织样本。因此， LS代表了阿托伐他汀的随机对照试验的一个新的和高度易处理的替代生物标志物终点 降低发生肝细胞癌的风险。 在这项提案中，我们将在60名代偿性肝硬变患者中进行II期随机对照试验，旨在测试 我们验证的48周阿托伐他汀降低肝癌风险的有效性、安全性和耐受性 请看我的个人资料。所有受试者将在筛查肝活检时定义高危偏最小二乘法，受试者将随机 在48周的研究期间，分配到2个研究组中的1个：阿托伐他汀20毫克/天或安慰剂，适当 在48周期间进行监测，随后在48周进行重复活组织检查，以评估PLS的改善情况 侧写。我们还将通过评估阿托伐他汀是否与其目标充分接触来确认 药代动力学/药效学，前/肿瘤标志物，以及河马-YAP途径的改变。我们 假设阿托伐他汀组在48周治疗结束时基于偏最小二乘法的肝细胞癌风险水平降低。 如果阿托伐他汀治疗有效、安全和耐受性良好，它可能成为第一种化学预防药物 旨在防止在美国日益增长的患者群体中发生肝细胞癌，由最小二乘法指导。 他们受到肝硬变的影响，有很高的风险出现这种毁灭性的并发症。