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: 10478274
• 负责人: RAYMOND T CHUNG
• 金额: $ 69.77万
• 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/10478274
• 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; 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; Placebo Control; 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 inflammation; 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.

项目摘要 在全球范围内，肝细胞癌（HCC）代表了第五大常见的癌症和第二个领先的癌症 与癌症相关的死亡率的原因。在美国，HCC发病率和死亡率都在令人震惊 步伐。尽管存在这些趋势，但HCC的治疗选择仍然有限，预后很严峻，有 5年的生存率仅为15％。因此，确定有效的策略以防止事件发展 HCC代表了关键的公共卫生需求。越来越多的临床前和基于人口的观测体 现在的数据表明，亲脂性汀类药物，尤其是雌雄同体，可减少肝炎症，细胞 增殖和癌细胞侵袭，并降低HCC的发生，部分通过对相关途径作用 包括河马信号通路。但是，尽管有这些有希望的数据，但已设计良好的随机性 尚未报告Atorvastatin的HCC预防的对照试验（RCT）。从历史上看，可行性 HCC预防试验受到大量样本量的限制，并需要长时间的随访时间来评估 目标端点。然而，最近，我们的小组衍生并验证了186基因的表达预后 肝脏签名（PLS），代表HCC的准确，可重复且高度可靠的替代生物标志物 所有主要的肝硬化病毒和非病毒病因的多个国际人群的风险。此外，我们还有 证明PLS的治疗调制可以准确地概括未来发生事件的风险 HCC肿瘤，包括体内和确认性人类研究。最后，我们和其他人在人类中证明了 肝组织样品atorvastatin通过作用于河马途径来部分调节PL。因此， PLS代表了一种新颖且高度可处理的替代生物标志物端点 降低事件HCC风险。 在此提案中，我们将对60例补偿肝硬化患者进行II期RCT，旨在测试 降低HCC风险的48周Atorvastatin的功效，安全性和耐受性，由我们的经过验证的定义 PLS配置文件。所有受试者将在筛查肝活检时定义高风险PL，并且受试者将是随机的 分配给2个研究臂中的1个48周研究期：Atorvastatin 20mg/天或安慰剂，适当 监测为期48周的监测，然后在第48周重复活检，以评估PLS的改进 轮廓。我们还将确认阿托伐他汀是否通过评估可以充分地参与其目标 药代动力学/药效学，前/肿瘤标记和河马途径的改变。我们 假设基于PLS的HCC风险水平在48周治疗结束时Atorvastatin臂的降低。 如果阿托伐他汀治疗有效，安全且耐受性良好，则可能成为第一个化学预防剂 旨在防止在美国越来越多的患者人群中的PLS指导的HCC的发展 受到肝硬化的影响，并且有这种毁灭性并发症的高风险。