Early Detection of HCC Among Veterans With Liver Cirrhosis

肝硬化退伍军人中肝癌的早期发现

基本信息

批准号：
10686004
负责人：
Srikanta Dash
金额：
--
依托单位：
SOUTHEAST LOUISIANA VETERANS HEALTH CARE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10686004
关键词：
Affinity African American population Alcohol consumption Antiviral Agents Applications Grants Area Autophagocytosis Autophagosome Biological Assay Biological Markers Blood Cirrhosis Data Detection Development Diabetes Mellitus Early Diagnosis Enrollment Enzyme-Linked Immunosorbent Assay Excision Fibrosis Funding GPC3 gene Genetic Transcription Guidelines Hepatitis C Hepatitis C virus Hepatocyte Hispanic Hsc70 protein Human Impairment Incidence Interferons Laboratories Learning Liver Liver Cirrhosis Lysosomes Malignant - descriptor Malignant neoplasm of liver Measurement Measures Mediating Medical center Metabolic syndrome Methods MicroRNAs Molecular Chaperones Monitor Multicenter Studies Multivesicular Body Obesity Organ Pathway interactions Patients Performance Play Population Primary carcinoma of the liver cells Prognosis Proteins Publishing ROC Curve Race Research Risk Risk Factors Role Sensitivity and Specificity Series Serum Signal Transduction Stress Surveillance Methods Testing Therapeutic Intervention Transplantation Veterans Viral Virus Diseases alpha-Fetoproteins biological adaptation to stress chronic liver disease diagnostic value early detection biomarkers endoplasm exosome hepatoprotective imaging modality improved indexing inhibition of autophagy liver development non-alcoholic fatty liver disease patient population performance tests preservation response specific biomarkers standard of care therapeutically effective ultrasound validation studies

项目摘要

Hepatocellular carcinoma (HCC) is a primary malignant cancer of the liver that most often develops in the background of liver cirrhosis (1,2). Hepatitis C virus (HCV) infection remains the major cause of liver cirrhosis and HCC among US Veterans (3,4). Recent advances in antiviral treatment have allowed an increasing number of cirrhotic patients to be cured with interferon (IFN)-free direct-acting antivirals (DAAs) (5,6). In the coming years, hepatitis C eradication is expected to decrease, but not eliminate, the risk of HCC among cirrhotic patients (7,8). The risk of HCC remains elevated post HCV clearance among patients with advanced fibrosis or cirrhosis and is also magnified by other risk factors such as daily alcohol intake, obesity, metabolic syndrome, diabetes, and race (African Americans or Hispanic) (7-16). HCC detected at an early stage can be effectively treated with transplantation, resection or even loco-regional therapies, but HCC detected at a late stage has a poor prognosis. The current HCC surveillance methods include liver ultrasound every six months with option of serum AFP (AASLD guideline). However, these methods lack the specificity and sensitivity needed to detect HCC at an early stage. Therefore, the development of a noninvasive, serum-based biomarker will allow early HCC detection and effective therapeutic intervention. This multicenter grant application proposes to test the performance of liver- specific serum biomarkers, together with standard-of-care tests including liver ultrasound, alpha-fetoprotein (AFP) AFP-L3 and DCP for HCC detection to monitor HCC risk among cirrhotic patients. This validation study will be performed by enrolling 2000 cirrhotic VA patients (HCV and non-HCV) from six different VA medical centers. Based on the incidence rate of HCC among the cirrhotic population, we anticipate >50 HCC cases will be detected at an early stage. Our hypothesis is that liver cirrhosis patients who do not resolve the ER-stress response will remain at an increased risk of HCC and therefore continue secreting HCC-specific exosomes that are enriched in glypican-3 and HSC70 (heat shock cognate protein 70) into the blood. Since the stress response depletes miRNA-122 transcription, we postulate that measurement of serum miRNA-122 levels will provide a powerful organ-specific biomarker for early prediction of cirrhosis regression after HCV cure. This application will explore the performance of HCC-specific exosome biomarkers, miRNA-122 and their additional benefit to serum AFP testing and liver ultrasound to improve surveillance of HCC and early detection of HCC. This hypothesis will be tested using the following Specific Aims: Aim 1 will determine the performance of serum exosomal cargoes (glypican-3, HSC70 and CD63) along with liver ultrasound, AFP, AFP-L3, DCP as a combined biomarker platform for the early detection of HCC among Veterans with liver cirrhosis after HCV cure using a longitudinal multicenter study. Aim 2 will develop a longitudinal multicenter study to determine the benefit of early HCC surveillance using the combination of exosomal biomarkers (glypican-3, HSC70 and CD63), serum miRNA-122 and non-exosomal (liver ultrasound, AFP, AFP-L3, DCP) for the early detection of HCC among Veterans with liver cirrhosis related to non-alcoholic fatty liver disease (NAFLD). Aim 3 will investigate whether measurement of liver specific miRNA- 122 levels in the serum along with noninvasive tests (FIB-4 index, APRI score and FibroScan) could increase the power of early assessment of cirrhosis regression or risk for persistent cirrhosis after HCV cure among Veterans with liver cirrhosis. If this application is selected for funding an exosome-based biomarker platform will be developed for early HCC detection among cirrhotic VA patients.

肝细胞癌（HCC）是一种原发性肝脏恶性肿瘤，最常发生于肝硬化背景(1,2)。丙型肝炎病毒（HCV）感染仍然是肝硬化的主要原因美国退伍军人中的肝癌和肝癌 (3,4)。抗病毒治疗的最新进展使越来越多的人的肝硬化患者可使用不含干扰素 (IFN) 的直接作用抗病毒药物 (DAA) 治愈 (5,6)。在即将到来的多年来，丙型肝炎的根除预计会降低（但不会消除）肝硬化患者患 HCC 的风险 (7,8)。在晚期纤维化或肝硬化患者中 HCV 清除后，HCC 的风险仍然较高并且还会因其他危险因素而放大，例如每日饮酒、肥胖、代谢综合征、糖尿病、和种族（非裔美国人或西班牙裔）(7-16)。早期发现的肝癌可以有效治疗移植、切除甚至局部治疗，但晚期发现的肝癌预后较差。目前的 HCC 监测方法包括每六个月进行一次肝脏超声检查，并可选择血清 AFP （AASLD 指南）。然而，这些方法缺乏早期检测 HCC 所需的特异性和敏感性。阶段。因此，开发一种非侵入性、基于血清的生物标志物将有助于早期检测 HCC 有效的治疗干预。这项多中心拨款申请旨在测试肝脏的性能特定血清生物标志物，以及标准护理测试，包括肝脏超声、甲胎蛋白 (法新社) AFP-L3 和 DCP 用于 HCC 检测，以监测肝硬化患者的 HCC 风险。本验证研究将通过招募来自六个不同 VA 医疗中心的 2000 名肝硬化 VA 患者（HCV 和非 HCV）来进行中心。根据肝硬化人群中 HCC 的发病率，我们预计将有超过 50 例 HCC 病例及早发现。我们的假设是，未解决 ER 应激的肝硬化患者反应仍将导致 HCC 风险增加，因此会继续分泌 HCC 特异性外泌体血液中富含磷脂酰肌醇蛋白聚糖 3 和 HSC70（热休克同源蛋白 70）。由于应激反应耗尽 miRNA-122 转录，我们假设血清 miRNA-122 水平的测量将提供强大的器官特异性生物标志物，用于丙型肝炎治愈后肝硬化消退的早期预测。该应用程序将探索 HCC 特异性外泌体生物标志物 miRNA-122 的性能及其对血清的额外益处 AFP 检测和肝脏超声可改善 HCC 监测和 HCC 早期发现。这个假设将使用以下具体目标进行测试：目标 1 将确定血清外泌体货物的性能（glypican-3、HSC70 和 CD63）与肝脏超声、AFP、AFP-L3、DCP 作为组合生物标志物平台使用纵向多中心在 HCV 治愈后患有肝硬化的退伍军人中早期发现 HCC 学习。目标 2 将开展一项纵向多中心研究，以确定早期 HCC 监测的益处外泌体生物标志物（glypican-3、HSC70 和 CD63）、血清 miRNA-122 和非外泌体的组合（肝脏超声、AFP、AFP-L3、DCP）用于早期发现肝硬化相关退伍军人中的 HCC 到非酒精性脂肪肝（NAFLD）。目标 3 将研究肝脏特异性 miRNA 的测量是否血清中 122 的水平以及非侵入性测试（FIB-4 指数、APRI 评分和 FibroScan）可能会增加 HCV 治愈后早期评估肝硬化消退或持续性肝硬化风险的作用患有肝硬化的退伍军人。如果该申请被选择资助基于外泌体的生物标志物平台旨在用于肝硬化 VA 患者的早期 HCC 检测。