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 在世界范围内，肝细胞癌（HCC）是第五大常见癌症，也是第二大恶性肿瘤。 癌症相关死亡的原因。在美国，HCC的发病率和死亡率都在以惊人的速度增加， 步伐。尽管有这些令人担忧的趋势，HCC的治疗选择仍然有限，预后也很严峻， 五年存活率只有15%因此，确定有效的战略，以防止事件的发展， HCC是一种关键的公共卫生需求。越来越多的临床前和基于人群的观察性研究 现在的数据表明，亲脂性他汀类药物，特别是阿托伐他汀， 增殖和癌细胞侵袭，并降低HCC的发病率，部分是通过作用于相关途径， 包括Hippo-YAP信号通路。然而，尽管有这些有希望的数据，设计良好的随机 阿托伐他汀预防HCC的对照试验（RCT）尚未报道。从历史上看， 由于需要大样本量和长时间的随访来评估， 目标端点。然而，最近，我们的研究小组已经推导并验证了一个186个基因表达的预后指标。 肝脏特征（PLS），代表HCC的准确，可重复和高度可靠的替代生物标志物 多个国际队列中所有主要病毒性和非病毒性肝硬化病因的风险。您因前述 证明了PLS的治疗调节准确地概括了未来发生事件的风险 HCC肿瘤，包括体内和确证性人类研究。最后，我们和其他人已经证明了在人类 肝组织样品中，阿托伐他汀调节PLS的一部分，通过对Hippo-YAP途径的作用。因此 PLS代表阿托伐他汀RCT的一种新的高度易处理的替代生物标志物终点， 降低HCC风险。 在本提案中，我们将在60例代偿性肝硬化患者中进行II期随机对照试验，旨在检测 阿托伐他汀治疗48周降低HCC风险的有效性、安全性和耐受性， PLS配置文件。所有受试者将在筛选肝活检时具有高风险PLS，并且受试者将被随机分组。 在48周的研究期内，被分配至2个研究组之一：阿托伐他汀20 mg/天或安慰剂， 监测48周，然后在第48周重复活检，以评估PLS的改善 profile.我们还将通过评估阿托伐他汀是否充分发挥其作用， 药代动力学/药效学、肿瘤前/肿瘤标志物和Hippo-YAP途径的改变。我们 假设在48周治疗结束时，阿托伐他汀组基于PLS的HCC风险水平降低。 如果阿托伐他汀治疗有效、安全且耐受性好，它可能成为第一种化学预防剂 在PLS的指导下，在美国不断增长的患者人群中预防HCC的发展。 他们患有肝硬化，并且是这种毁灭性并发症的高危人群。