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

基本信息

批准号：
10703699
负责人：
Lopa Mishra
金额：
$ 76.1万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-14 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10703699
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

项目摘要

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，我们建议验证组织和基于血液的组合生物标志物面板，该面板源自功能途径特异性研究，以改善肝癌的早期检测[肝细胞癌（HCC）]和根据他们发展HCC的风险来分层人群。在早期阶段，HCC可以治愈。一次高级HCC与高死亡率有关。大多数早期的HCC都未被发现，证明了挑战在预测和诊断早期HCC中。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集（TCGA），小鼠模型和人组织/细胞系研究的数据，我们确定了可以通过以下生物标志物的改变来识别特定的高风险人群：EPCAM，骨桥蛋白（OPN），polo样激酶1（PLK1）TGF-β和DNA修复构件。我们已经建立了 4个转化研究中心（TRC）的多中心财团：约翰·霍普金斯大学（TRC1），乔治华盛顿大学（TRC2），德克萨斯大学医学博士安德森癌症中心（TRC3），夏威夷大学（TRC4）。这4个TRC将与NCI合作实施一个多机构的框架来收集来自各种定义明确的肝脏病理的患者的最高质量生物测量并进行特定生物标志物验证研究，用于早期检测HCC和肝硬化患者的风险分层。基于我们在人类肝病中的功能性临床前模型和试验研究的中心假设样本是上述标记中的改变导致HCC，并且这些变化的异常表达可能导致早期检测HCC以及风险分层。具体而言，将评估以下生物标志物面板（a）组织EPCAM，OPN，PLK1水平（面板1，项目1，TRC1），（b）TBR2，SPTBN1，FANCD2的组织水平和SIRT6（面板2，项目2 TRC2）。（c）在TRC1中测试血清标记（面板3，EPCAM，OPN，TGF-β）和2; （d）在循环肿瘤细胞（CTC）中，突变分析（面板4，SMAD4和SPTBN1，项目2，TRC2）将进行表面波形蛋白（CSV）（面板5，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，还将与NCI，中国和外部队列合作，其中包括EDRN样品。这4个项目将共同解决：AIM 1：EDRN 2阶段研究（在组织中找到当前HCC的标记）仅使用面板1和2。所有样品都是回顾性的，在患者（病例）和对照组中收集。目标2： EDRN第2期研究仅在面板3、4和5上进行。在这里，所有样品都是回顾性的，收集在当前情况和当前控制。 AIM 3：EDRN第三阶段研究（预测未来的面板3标记使用纵向数据（回顾性和前瞻性）在血液中开发HCC）。收集数据在参与者开发HCC之前，他们会随着时间的推移而遵循他们发展HCC，并且多次发展在肿瘤发作之前，收集并随着时间的推移收集标记数据。此外，我们将维护和共享生物座席，并与肝癌转化研究网络中的其他中心合作。

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Accuracy of Milan, University of California San Francisco, and Up-To-7 Criteria in Predicting Tumor Recurrence Following Deceased-Donor Liver Transplant in Patients With Hepatocellular Carcinoma.

DOI：
10.6002/ect.2017.0288
发表时间：
2020-08
期刊：
Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation
影响因子：
0
作者：
Saberi B;Garonzik-Wang J;Ma M;Ajayi T;Kim A;Luu H;Jakhete N;Pustavoitau A;Anders RA;Georgiades C;Kamel I;Ottmann S;Philosophe B;Cameron AM;Gurakar A
通讯作者：
Gurakar A

A small molecule Hedgehog agonist HhAg1.5 mediated reprogramming breaks the quiescence of noninjured liver stem cells for rescuing liver failure.