Epigallocatechin gallate for prevention of lethal cirrhosis complications

总结 肝细胞癌（HCC）是肝硬化患者死亡的主要原因，且上升速度最快 美国的癌症死亡率由于现有疗法对已建立的HCC肿瘤的疗效有限， 患者的预后仍然很差，5年生存率低于15%。因此，肝硬化的HCC化学预防 可能是提高生存率最有效的策略。然而，尽管候选化学预防剂 在实验研究中，由于进行临床试验的后勤困难， 这需要大样本量和长随访时间。为了克服这一挑战，我们确定了预后肝脏 分泌组标记（PLSec）用于定量监测肝硬化中HCC风险水平的治疗调节 患者，并预测未来发生HCC的减少。在我们的研究中，PLSec已被用作替代终点。 正在进行和计划进行的HCC化学预防临床试验。我们在啮齿动物模型中进行的实验研究， 其他人认为表没食子儿茶素没食子酸酯（EGCG），一种绿色茶儿茶素，可以预防HCC的发展 没有任何不良事件。我们的肝硬化精密切割肝切片（PCLS）的离体器官型培养 患者显示EGCG抑制高风险特征，支持其临床相关性。基于这些 有希望的发现，我们的建议的目标是测试我们的假设，EGCG治疗安全地抑制 肝硬化患者的PLSec。目标1。评估EGCG在肝硬化患者中的安全性和有效性（II期 双盲安慰剂对照临床试验）。我们将在60名受试者中评估24周的EGCG治疗或安慰剂治疗。 根据基于临床变量的HCC风险升高的早期肝硬化患者（1：1随机化） 评分（FIB-4指数）和PLSec。将每月监测参与者的不良事件。血清样本将 在治疗前、治疗期间和治疗结束时获得。主要终点：测量的风险水平降低 PLSec（delta-PLSec）。次要终点：安全性特征、生活质量变化。探索性终点： 知情同意的受试者治疗期间PLSec、HCC风险相关标志物免疫组织化学的变化 肝活检和偶发性肝细胞癌目标2.确定肝硬化患者对表没食子儿茶素没食子酸酯反应的相关因素。 我们将评估治疗前PLSec和临床组织学变量;治疗中PLSec调节和 表没食子儿茶素没食子酸酯及其代谢物的血浆浓度与主要终点的相关性。我们还将 通过声学弹性成像评估FIB-4指数和肝脏硬度测量的调节， 作为监测表没食子儿茶素没食子酸酯效果的替代临床终点，我们期望建立新的肝癌化学预防 随着膳食补充剂用于随后的关键III期临床试验，以实现该方法的临床转化， 这将有助于通过使个体- 以风险为基础，分子为靶点，安全的化学预防这种致命的癌症。

Summary Hepatocellular carcinoma (HCC) is the leading cause of death in patients with cirrhosis, and the fastest rising cancer mortality in the U.S. Due to the limited efficacy of existing therapies for established HCC tumors, prognosis for patients remains poor, with five-year survival under 15%. Thus, HCC chemoprevention in cirrhosis is likely the most impactful strategy to improve survival. However, despite the candidate chemopreventive agents suggested in experimental studies, it remains an unmet need due to logistical difficulty in conducting clinical trials that require large sample size and long follow-up time. To overcome the challenge, we identified Prognostic Liver Secretome signature (PLSec) to quantitatively monitor therapeutic modulation of HCC risk level in cirrhosis patients, and predict reduction of future incident HCC. PLSec has been used as a surrogate endpoint in our ongoing and planned HCC chemoprevention clinical trials. Experimental studies in rodent models by us and others suggested that epigallocatechin gallate (EGCG), a green tea catechin, prevents HCC development without any adverse events. Our ex vivo organotypic culture of precision-cut liver slice (PCLS) from cirrhosis patients revealed suppression of high-risk signature by EGCG, supporting its clinical relevance. Based on these promising findings, the goal of our proposal is to test our hypothesis that EGCG treatment safely suppresses PLSec in patients with cirrhosis. Aim 1. Evaluate safety and efficacy of EGCG in cirrhosis patients (phase II double-blinded placebo-controlled clinical trial). We will evaluate 24-week EGCG treatment or placebo in 60 patients (1:1 randomization) with early-stage cirrhosis enriched for elevated HCC risk by a clinical variable-based score (FIB-4 index) and PLSec. Participants will be monitored monthly for adverse events. Serum samples will be obtained before, during, and at the end of treatment. Primary endpoint: reduction of risk level as measured by PLSec (delta-PLSec). Secondary endpoints: safety profile, change in quality of life. Exploratory endpoints: change in on-treatment PLSec, immunohistochemistry of HCC-risk-related markers for participants consented for liver biopsy, and incident HCC. Aim 2. Identify factors associated with response to EGCG in cirrhosis patients. We will evaluate pre-treatment PLSec and clinico-histological variables; on-treatment PLSec modulation and plasma concentration of EGCG and its metabolites for their association with the primary endpoint. We will also assess modulation of the FIB-4 index and liver stiffness measurement by acoustic elastography as potential alternative clinical endpoints to monitor effect of EGCG, We expect to establish novel HCC chemoprevention with a dietary supplement for subsequent pivotal phase III clinical trial toward clinical translation of this approach, which will contribute to a transformative improvement in the outcome of patients with HCC by enabling individual- risk-based, molecular-targeted, and safe chemoprevention of this deadly cancer.