Exosomal biomarkers for the early detection of hepatocellular carcinoma

用于早期检测肝细胞癌的外泌体生物标志物

• 批准号: 10660885
• 负责人: Ajay Goel
• 金额: $ 74.53万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-08 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10660885
• 关键词: Alcohol abuse; Bioinformatics; Biological Assay; Biological Markers; Blood; Blood Specimen Collection; Cancer Etiology; Cell Line; Cells; Cessation of life; Chronic Hepatitis; Circulation; Clinical; Collection; Data; Death Rate; Detection; Diagnostic; Disease; Early Diagnosis; Early identification; Early treatment; Etiology; Evaluation; Excretory function; Hepatic; Human; Impairment; Incidence; Individual; Liver; Liver Cirrhosis; Machine Learning; Malignant Neoplasms; Malignant neoplasm of liver; Messenger RNA; Methodology; MicroRNAs; Modality; Molecular; Molecular Profiling; Mutation; Neoplasms; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Patients; Perception; Performance; Plasma; Population; Prevention; Primary carcinoma of the liver cells; Prospective cohort; Protocols documentation; Reproducibility; Research; Sampling; Sensitivity and Specificity; Small RNA; Specificity; Specimen; Standardization; Surveillance Methods; Systemic Therapy; Tissues; Translational Research; Tumor Markers; Viral; Virus; alpha-Fetoproteins; biomarker discovery; biomarker panel; circulating microRNA; clinically relevant; cohort; cost; diagnostic value; differential expression; early detection biomarkers; exosome; extracellular vesicles; fatty liver disease; genome-wide; high risk; imaging modality; liquid biopsy; liver function; microRNA biomarkers; mortality; nonalcoholic steatohepatitis; patient population; prognostic; prospective; resilience; screening; transcriptome sequencing; ultrasound

PROJECT SUMMARY: Liver cancer is estimated to afflict 42,230 individuals and result in approximately 30,230 deaths in the US in 2021. The incidence rates for liver cancer have more than tripled since 1980, making it the 5th leading cause of cancer- related deaths in the US. Approximately three-fourths of liver cancer cases are hepatocellular carcinoma (HCC). As for all cancers, detection of HCC at an earlier stage is critical to elicit the best chance of a cure. Early detection of HCC has significant potential to reduce mortality rates, due to the significant efficacy of local treatments for early-stage disease vs. systemic therapy for advanced-stage cancers. Although surveillance of patients at high- risk for HCC (e.g., those with chronic hepatitis or liver cirrhosis [LC]) is widely performed, the population of patients with HCC without viral etiologies is increasing because of insufficient screening for HCC. At present, alpha-fetoprotein (AFP) is the most widely used blood tumor marker; and hepatic ultrasound is a low-cost imaging method for surveillance of HCCs. However, both approaches have limited sensitivity and specificity for detecting early-stage HCC, highlighting the imperative need to develop robust biomarkers for the early detection of HCC. Accumulating evidence indicates that dysregulation of microRNAs (miRNAs) occurs in all human cancers, including HCC. As biomarkers, miRNAs are more resilient than mRNAs, and are frequently deregulated even in the earliest stages of neoplasia. Furthermore, the recent discovery that cancers actively excrete small extracellular vesicles, called exosomes, has brought additional enthusiasm to this burgeoning translational research topic. While exosomes are considered to reflect their respective cells-of-origin, their use in biomarker research has been hampered due to lack of standardized protocols for their isolation and purification, use of cell line-derived, but not patient-derived specimens for biomarker discovery; and lack of biomarker discovery in cancer-derived exosomes from matched tissues and plasma specimens. Furthermore, despite the perception that exosomal-miRNAs (exo-miRNAs) may be superior to circulating cell-free miRNAs (cf-miRNAs), no studies have undertaken an effort to directly compare these two types, to support or negate their superiority as disease biomarkers. In this proposal, we will address these concerns by undertaking the following Specific Aims. Aim 1: Discover candidate cf-miRNA and exo-miRNA biomarkers using small RNA-Seq in matched tissue and plasma from patients with early-stage HCC vs. controls. Aim 2: Develop a biomarker panel composed of cf-miRNAs and exo-miRNAs for the identification of patients with HCC in an independent cohort. Aim 3: Clinically validate the optimized panel of non-invasive plasma miRNA biomarkers in a large prospective cohort of patients with HCC. If successful, this proposal will provide molecular characterization of cell-free and exosomal miRNAs as liquid biopsy biomarkers, which may allow early-detection of HCC using a non-invasive, and inexpensive assay.

项目总结： 据估计，2021年美国有42,230人罹患肝癌，并导致约30,230人死亡。 自1980年以来，肝癌的发病率增加了两倍多，成为第五大癌症原因- 美国的相关死亡事件。大约四分之三的肝癌病例是肝细胞癌。 对于所有癌症来说，在早期阶段发现肝癌对于获得最好的治愈机会至关重要。早期发现 肝癌的局部治疗具有显著的降低死亡率的潜力，这是因为局部治疗对 晚期癌症的早期疾病与系统治疗。尽管对处于高危状态的患者进行了监测- 患肝癌的风险(例如，患有慢性肝炎或肝硬变的人[LC])广泛存在， 由于对肝细胞癌筛查不足，无病毒病因的肝细胞癌患者正在增加。目前， 甲胎蛋白(AFP)是最广泛使用的血液肿瘤标记物；而肝脏超声是一种低成本的成像方法 监测碳氢化合物的方法。然而，这两种方法对检测的敏感性和特异性都有限。 早期肝细胞癌，突出了开发强大的生物标志物用于肝细胞癌早期检测的迫切需要。 越来越多的证据表明，microRNAs(MiRNAs)的调节失调存在于所有人类癌症中， 包括肝细胞癌。作为生物标志物，miRNAs比mRNAs更具弹性，即使在 肿瘤形成的最早阶段。此外，最近发现癌症主动排泄的小分子 胞外囊泡，称为外体，为这种蓬勃发展的翻译带来了额外的热情 研究课题。虽然外切体被认为反映了它们各自的起源细胞，但它们在生物标记物中的用途 由于缺乏分离和纯化、细胞使用的标准化方案，研究受到了阻碍 用于生物标记物发现的来自品系的但不是来自患者的样本；以及在 从匹配的组织和血浆样本中提取的癌症外切体。此外，尽管人们认为 没有研究表明，外体miRNAs(exo-miRNAs)可能优于循环中的无细胞miRNAs(cf-miRNAs) 致力于直接比较这两种类型，支持或否定它们作为疾病的优越性 生物标志物。在这项提案中，我们将通过实现以下具体目标来解决这些关切。目标1： 在匹配的组织和血浆中利用小RNA-Seq发现候选的cf-miRNA和exo-miRNA生物标志物 来自早期肝细胞癌患者和对照组。目的2：建立由cf-miRNAs和cf-miRNAs组成的生物标志物小组 外源miRNAs用于在独立队列中识别肝细胞癌患者。目标3：临床验证 一组优化的非侵入性血浆miRNA生物标记物在一大批肝细胞癌患者中的应用。 如果成功，这项提议将提供液体形式的无细胞和外体miRNAs的分子特征 活检生物标记物，这可能允许使用一种非侵入性的、廉价的分析来早期发现肝细胞癌。