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.

项目概要： 据估计，2021年美国有42，230人患有肝癌，约30，230人死亡。 自1980年以来，肝癌的发病率增加了两倍多，使其成为第五大癌症原因- 在美国相关的死亡。大约四分之三的肝癌病例是肝细胞癌（HCC）。 对于所有癌症，在早期阶段检测HCC对于获得最佳治愈机会至关重要。早期检测 由于局部治疗的显著疗效， 早期疾病与晚期癌症的全身治疗。尽管对患者的监测处于高水平- HCC的风险（例如，慢性肝炎或肝硬化患者[LC]）广泛进行， 由于对HCC的筛查不足，无病毒病因的HCC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志物;肝脏超声是一种低成本的成像方法， 监测HCC的方法。然而，这两种方法都具有有限的灵敏度和特异性，用于检测 早期HCC，强调迫切需要开发用于早期检测HCC的稳健生物标志物。 越来越多的证据表明，所有人类癌症中都存在微小RNA（miRNAs）的失调， 包括HCC。作为生物标志物，miRNA比mRNA更有弹性，即使在环境中也经常被解除管制 肿瘤形成的最早阶段此外，最近发现，癌症积极排泄小 细胞外囊泡，称为外来体，带来了额外的热情，这一新兴的翻译 的研究课题虽然外泌体被认为反映了它们各自的起源细胞，但它们在生物标志物中的用途是不确定的。 由于缺乏标准化的分离和纯化方案，细胞的使用， 用于生物标志物发现的系源性标本，而非患者源性标本; 来自匹配组织和血浆样本的癌症来源的外来体。此外，尽管人们认为 exosomal-miRNAs（exo-miRNAs）可能上级循环无细胞miRNAs（cf-miRNAs），没有研究表明 我曾努力直接比较这两种类型，以支持或否定它们作为疾病的优越性 生物标志物。在本提案中，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使用小RNA-Seq发现候选cf-miRNA和exo-miRNA生物标志物 与对照组相比。目的2：开发由cf-miRNAs和 exo-miRNAs用于在独立队列中鉴定HCC患者。目标3：临床验证 在一个大型的HCC患者前瞻性队列中，使用一组优化的非侵入性血浆miRNA生物标志物。 如果成功，该提议将提供无细胞和外泌体miRNAs作为液体的分子表征。 活检生物标志物，这可能允许使用非侵入性和廉价的测定来早期检测HCC。