Pathway Specific Functional Biomarkers for the Early Detection of Liver Cancer

用于肝癌早期检测的途径特异性功能生物标志物

• 批准号: 10239028
• 负责人: Lopa Mishra
• 金额: $ 65.24万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-14 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239028
• 关键词: Abbreviations; Adaptor Signaling Protein; Address; Age; Area; Area Under Curve; Automobile Driving; Biological Markers; Blood; Body mass index; Cell Adhesion Molecules; Cell Line; Cell surface; Cells; Center for Translational Science Activities; Characteristics; China; Chronic Active Hepatitis; Cirrhosis; Collaborations; DNA Repair; DNA Repair Gene; Data; Development; Diagnostic; Disease; Early Detection Research Network; Early Diagnosis; Effect Modifiers (Epidemiology); Enzymes; Etiology; FANCD2 protein; Foundations; Future; Gastroenterology; Genes; Hawaii; Hepatitis B; Hepatitis C; Hepatology; Human; Image; Infection; Inflammatory; Lead; Liver; Liver diseases; Longitudinal cohort study; MADH4 gene; Malignant Neoplasms; Malignant neoplasm of liver; Mus; Mutation; Mutation Analysis; Neoplasm Circulating Cells; PLK1 gene; Participant; Pathology; Pathway interactions; Patients; Phase; Phenocopy; Pilot Projects; Plasma; Population; Pre-Clinical Model; Predictive Value; Primary carcinoma of the liver cells; Proteins; ROC Curve; Race; Receiver Operating Characteristics; Reproducibility of Results; Research; Research Design; Risk; Sampling; Screening for Hepatocellular Cancer; Serum; Serum Markers; Signal Transduction; Sirtuins; Smoking Status; Surface; Symptoms; TACSTD1 gene; TERC gene; TP53 gene; Testing; The Cancer Genome Atlas; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Translational Research; Universities; University of Texas M D Anderson Cancer Center; Vimentin; Washington; Work; adenoma; alpha-Fetoproteins; assay development; base; beta Spectrin; biobank; biomarker discovery; biomarker panel; biomarker validation; cancer cell; candidate marker; candidate validation; case control; circulating biomarkers; cohort; combinatorial; comorbidity; demographics; early detection biomarkers; genomic data; high risk; high risk population; human tissue; improved; liver development; liver inflammation; liver injury; member; mortality; mouse model; nonalcoholic steatohepatitis; osteopontin; patient stratification; patient subsets; phase 2 study; phase 3 study; polo-like kinase kinase 1; practical application; pre-clinical; preclinical study; predictive marker; premalignant; prospective; receptor; repository; risk stratification; sex; specific biomarkers; tissue biomarkers; tumor; tumorigenesis; validation studies

ABSTRACT Here, we propose to validate tissue and blood-based combinatorial biomarker panels, derived from functional pathway-specific studies, to improve the early detection of liver cancer [hepatocellular carcinoma (HCC)] and stratify populations according to their risk for developing HCC. In its early stages, HCC is curable; once advanced, HCC is associated with high mortality. Most early HCCs are undetected, demonstrating the challenge in predicting and diagnosing early HCC. Through preclinical studies that integrate analysis of human genomic data from The Cancer Genome Atlas (TCGA), mouse models, and human tissue/cell line studies, we determined that specific high-risk populations may be identified through alterations in the following biomarkers: EpCAM, Osteopontin (OPN), the polo-like kinase 1 (PLK1) the TGF-β and DNA repair members. We have established a multi-center consortium of 4 Translational Research Centers (TRCs): Johns Hopkins University (TRC1), George Washington University (TRC2), University of Texas MD Anderson Cancer Center (TRC3), University of Hawaii (TRC4). These 4 TRCs will work in collaboration with NCI to implement a multi-institutional framework to collect the highest quality biospecimens from patients with various well-defined liver pathologies and conduct specific biomarker validation studies for early detection of HCC and risk stratification of patients with cirrhosis. The central hypothesis, based upon our functional preclinical models and pilot studies in human liver disease samples, is that alterations in the above markers lead to HCC, and that aberrant expression of these can lead to early detection of HCC, as well as risk stratification. Specifically, the following biomarker panels will be assessed (a) Tissue EpCAM, OPN, PLK1 levels (Panel 1, Project 1, TRC1), (b) Tissue levels of TBR2, SPTBN1, FancD2 and Sirt6 (Panel 2, Project 2 TRC2). (c) Serum markers (Panel 3, EpCAM, OPN, TGF-β) will be tested in TRC1 and 2; (d) In circulating tumor cells (CTCs), mutational analyses (Panel 4, Smad4 and SPTBN1, Project 2, TRC2) and surface vimentin (CSV) (Panel 5, Project 3, TRC3) will be performed. Validation of candidate biomarkers (Project 4, TRC4) will also be done at TRC4, and also with collaborations in NCI, China and external cohorts, that include EDRN samples. The 4 projects will collectively address: Aim 1: EDRN Phase 2 studies (to find markers of current HCCs) in tissue only using panels 1 and 2. All samples are retrospective, collected in patients (cases) and controls. Aim 2: EDRN Phase 2 studies in blood only on panels 3, 4 and 5. Here, all samples are retrospective, collected in current cases and current controls. Aim 3: EDRN Phase 3 studies (Panel 3 markers that predict future development of HCC) in blood using longitudinal data (both retrospective and prospective). Data are collected before participants develop HCC, and they are followed over time to see who develops HCC, and multiple time points of marker data are collected and stored over time prior to tumor onset. In addition, we will maintain and share a biorepository, and collaborate with other Centers in the Translational Research Network for Liver Cancer.

摘要 在这里，我们建议验证基于组织和血液的组合生物标志物面板，来自功能性 途径特异性研究，以提高肝癌[肝细胞癌（HCC）]的早期检测， 根据患肝癌的风险对人群进行分层。在其早期阶段，HCC是可治愈的;一旦 晚期HCC与高死亡率相关。大多数早期HCC未被发现，这表明 预测和诊断早期HCC。通过整合人类基因组分析的临床前研究， 从癌症基因组图谱（TCGA）、小鼠模型和人类组织/细胞系研究中获得的数据，我们确定 特定的高风险人群可以通过以下生物标志物的改变来鉴定：EpCAM， 骨桥蛋白（OPN）、Polo样激酶1（PLK 1）、TGF-β和DNA修复成员。我们建立了 由4个转化研究中心（TRCs）组成的多中心联盟：约翰霍普金斯大学（TRC 1）、乔治 华盛顿大学（TRC 2）、德克萨斯大学医学博士安德森癌症中心（TRC 3）、夏威夷大学 （TRC4）。这4个TRCs将与NCI合作，实施一个多机构框架， 从具有各种明确的肝脏病理的患者中获得最高质量的生物标本，并进行特定的 生物标志物验证研究，用于HCC的早期检测和肝硬化患者的风险分层。 基于我们的功能性临床前模型和人类肝病的初步研究， 上述标志物的改变导致HCC，并且这些标志物的异常表达可导致HCC。 早期发现HCC，以及风险分层。具体而言，将评估以下生物标志物组 (a)组织EpCAM、OPN、PLK 1水平（组1，项目1，TRC 1），（B）TBR 2、SPTBN 1、FancD 2的组织水平 和Sirt 6（小组2，项目2 TRC 2）。(c)将在TRC 1中检测血清标志物（组3、EpCAM、OPN、TGF-β） （d）在循环肿瘤细胞（CTC）中，突变分析（组4，Smad 4和SPTBN 1，项目2，TRC 2） 和表面波形蛋白（CSV）（第5组，项目3，TRC 3）。候选生物标志物的验证 （项目4，TRC 4）也将在TRC 4完成，并与NCI、中国和外部队列合作， 包括EDRN样本 这4个项目将共同解决：目标1：EDRN第2期研究（寻找当前HCC的标志物） 仅使用面板1和2。所有样本都是回顾性的，在患者（病例）和对照组中收集。目标二： 仅在队列3、4和5中进行血液EDRN II期研究。在这里，所有样本都是回顾性的，收集于 当前病例和当前对照。目标3：EDRN 3期研究（预测未来的第3组标记物） HCC的发展）的纵向数据（回顾性和前瞻性）。收集数据 在参与者发生HCC之前，他们会被跟踪一段时间，看看谁会发生HCC， 在肿瘤发作之前随时间收集并存储标记数据点。此外，我们将继续保持和 共享一个生物储存库，并与肝癌转化研究网络中的其他中心合作。