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.

抽象的 在这里，我们建议验证基于组织和血液的组合生物标志物组，这些组合生物标志物组源自功能性 途径特异性研究，以提高肝癌 [肝细胞癌 (HCC)] 的早期检测和 根据患 HCC 的风险对人群进行分层。在早期阶段，HCC 是可以治愈的；一次 晚期，HCC 与高死亡率相关。大多数早期 HCC 未被发现，这表明了这一挑战 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 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 可以通过以下生物标志物的改变来识别特定的高危人群：EpCAM， 骨桥蛋白 (OPN)、polo 样激酶 1 (PLK1)、TGF-β 和 DNA 修复成员。我们已经建立了一个 由 4 个转化研究中心 (TRC) 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 TRC 将与 NCI 合作实施一个多机构框架来收集 从患有各种明确肝脏病理的患者中提取最高质量的生物样本，并进行特定的 用于早期检测 HCC 和肝硬化患者风险分层的生物标志物验证研究。 中心假设基于我们的功能性临床前模型和人类肝脏疾病的初步研究 样本中，上述标记物的改变会导致 HCC，并且这些标记物的异常表达会导致 早期发现 HCC 以及风险分层。具体来说，将评估以下生物标志物组 (a) 组织 EpCAM、OPN、PLK1 水平（图 1、项目 1、TRC1），(b) TBR2、SPTBN1、FancD2 的组织水平 Sirt6（第 2 组，项目 2 TRC2）。 (c) 血清标志物（Panel 3、EpCAM、OPN、TGF-β）将在 TRC1 中进行测试 和2； (d) 在循环肿瘤细胞 (CTC) 中，突变分析（第 4 组，Smad4 和 SPTBN1，项目 2，TRC2） 将执行表面波形蛋白 (CSV)（第 5 组，项目 3，TRC3）。候选生物标志物的验证 （项目 4，TRC4）也将在 TRC4 上完成，并与 NCI、中国和外部队列进行合作， 其中包括 EDRN 样本。 这 4 个项目将共同解决： 目标 1：组织中的 EDRN 第 2 期研究（寻找当前 HCC 的标志物） 仅使用第 1 组和第 2 组。所有样本都是回顾性的，收集于患者（病例）和对照组。目标 2： EDRN 2 期血液研究仅在第 3、4 和 5 组中进行。此处，所有样本都是回顾性的，收集于 当前的案例和当前的控制。目标 3：EDRN 第 3 期研究（预测未来的面板 3 标记） 使用纵向数据（回顾性和前瞻性）在血液中检测 HCC 的发展。收集数据 在参与者发展成 HCC 之前，对他们进行一段时间的跟踪，看看谁发展成 HCC，并且多次 在肿瘤发生之前随时间收集和存储标记数据点。此外，我们将维护并 共享生物储存库，并与肝癌转化研究网络的其他中心合作。