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，源于功能 途径特异性研究，以改善对肝癌[肝细胞癌(HCC)]和 根据人群发生肝细胞癌的风险对人群进行分层。在早期阶段，肝细胞癌是可以治愈的；曾经 晚期肝细胞癌与高死亡率相关。大多数早期的HCC都没有被检测到，这表明了挑战 在预测和诊断早期肝细胞癌中的作用。通过临床前研究整合人类基因组分析 来自癌症基因组图谱(TCGA)、小鼠模型和人类组织/细胞系研究的数据，我们确定 特定的高危人群可以通过以下生物标志物的变化来识别：EpCAM， 骨桥蛋白、Polo-like kinase1(PLK1)是转化生长因子-β和DNA修复成员.我们已经建立了一个 由4个翻译研究中心(TRCs)组成的多中心联盟：约翰霍普金斯大学(TRC1)，乔治 华盛顿大学(TRC2)、德克萨斯大学MD安德森癌症中心(TRC3)、夏威夷大学 (TRC4)。这4个储税券中心将与NCI合作，实施多机构框架，以收集 最高质量的生物检材来自各种明确的肝脏病理和进行特定 用于肝细胞癌早期检测和肝硬变患者风险分层的生物标记物验证研究。 中心假设，基于我们的功能性临床前模型和人类肝病的初步研究 样本中，上述标记物的改变会导致肝细胞癌，而这些标记物的异常表达可能导致 肝细胞癌的早期发现，以及风险分层。具体地说，将评估以下生物标记小组 (A)组织EpCAM、OPN、PLK1水平(小组1，项目1，TRC1)，(B)组织中TBR2、SPTBN1、FANCD2水平 和SIRT6(小组2，项目2 TRC2)。(C)将在TRC1中检测血清标志物(Panel 3、EpCAM、OPN、转化生长因子-β) 和2；(D)循环肿瘤细胞(CTCs)，突变分析(小组4，Smad4和SPTBN1，项目2，TRC2) 和表面波形蛋白(CSV)(面板5，项目3，TRC3)将被执行。候选生物标志物的验证 (项目4，TRC4)也将在TRC4上完成，并将与国家预防犯罪中心、中国和外部队列合作， 其中包括EDRN样本。 这4个项目将共同涉及：目标1：EDRN阶段2研究(寻找组织中当前HC的标志物) 仅使用第一组和第二组。所有样本都是回溯性的，收集在患者(病例)和对照中。目标2： EDRN第二阶段研究仅在第3、4和5板上进行。在这里，所有样本都是回顾性的，收集在 当前病例和当前对照。目标3：EDRN阶段3研究(小组3预测未来的标记 在血液中使用纵向数据(包括回顾数据和前瞻性数据)。收集数据 在参与者患上肝癌之前，随着时间的推移，他们会被跟踪，看看谁会患上肝癌，并多次 标记物的数据点在肿瘤发病前随着时间的推移被收集和存储。此外，我们将维护和 共享一个生物库，并与肝癌转化研究网络中的其他中心合作。