Early Targets in Progression of Barrett's Esophagus to Esophageal Adenocarcinoma

巴雷特食管进展为食管腺癌的早期目标

基本信息

批准号：
10155436
负责人：
JOEL H RUBENSTEIN
金额：
$ 105.33万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10155436
关键词：
Accounting Address Adenocarcinoma Advisory Committees Appearance Barrett Esophagus Barrett&apos s neoplasia Binding Biochemistry Budgets Candidate Disease Gene Cell surface Cells Center for Translational Science Activities Clinical Clinical Data Clinical Research Communication Contracts Copy Number Polymorphism DNA DNA Sequence Alteration DNA copy number Dana-Farber Cancer Institute Data Detection Developed Countries Disease Endoscopes Endoscopy Esophageal Adenocarcinoma Esophagogastric Junction Esophagus Excision Fiber Formalin Foundations Freezing Gene Expression Gene Expression Alteration Gene Expression Profiling Gene Targeting Genes Genomics Goals Grant Human Image Immunohistochemistry Incidence Individual Institution Investigational New Drug Application Label Lesion Ligands Light Longitudinal cohort Malignant Neoplasms Malignant neoplasm of esophagus Medical Methodology Michigan Mission Molecular Target Mucous Membrane Mutation Neoplasms Operative Surgical Procedures Outcome Paraffin Embedding Patient Recruitments Patients Peptides Performance Pharmacology and Toxicology Pilot Projects Plasma Preventive measure Process Protocols documentation Research Research Personnel Research Project Grants Resources Reverse Transcriptase Polymerase Chain Reaction Risk Screening for cancer Sensitivity and Specificity Serum Spatial Distribution Specimen Survival Rate Telomerase Testing Therapeutic Intervention Time Tissue Microarray Tissues Translational Research Universities Update Washington biobank clinical translation cohort data repository dimer flexibility gastroesophageal junction adenocarcinoma genomic tools human subject imaging agent imaging modality improved in vivo imaging innovation monomer novel overexpression patient registry premalignant programs risk stratification sample collection spectrograph synergism transcriptome sequencing tumor heterogeneity virtual

项目摘要

- Project Summary/Abstract Recently, the incidence of esophageal (EAC) and gastro-esophageal junction (GEJAC) adenocarcinoma has increased dramatically, and have a poor 5-year survival rate of less than 15%. When detected early, these patients can have a good clinical outcome following surgery. These observations underscore the importance of early cancer detection. Patients with Barrett's esophagus (BE) are known to be at increased risk. Our overarching goal is to advance new methods of imaging to visualize the effects of spatial distribution of genetic alterations in BE by using novel imaging methods to evaluate tumor heterogeneity on the progression toward EAC. We propose a multi-institutional, trans-disciplinary, translational Research Center in the Barrett's Esophagus Translational Research Network (BETRNet). Our mission is to build on our expertise in genomic characterization, peptide biochemistry, and clinical translation to achieve our ultimate goal to perform early cancer detection at an early stage where therapeutic intervention can be most effective. We will identify a complementary panel of genes that are overexpressed on the cell surface and will be used to develop and validate new peptide imaging agents. The targets chosen will address 3 important clinical needs: 1) Real-time endoscopic identification of pre-malignant lesions and early stage cancer to guide endoscopic resection; 2) Risk stratification of BE patients for timing of endoscopic surveillance; and 3) Detection of gastro- esophageal junction adenocarcinomas in patients without endoscopic appearance of BE. We will use state-of-the-art genomic tools to to identify early overexpressed gene targets that arise in progression of BE to EAC by providing comprehensive analyses of gene expression alterations, DNA copy number variation, and genetic mutations. We will select candidate genes that are expressed on the cell surface where they can be endoscopically imaged in vivo. We will rigorously validate the panel of candidate targets with quantitative RT-PCR and immunohistochemistry on tissue microarrays using an independent cohort of human esophagus specimens. We will use these targets to first identify and validate monomer peptides that are highly specific. We will then arrange monomer peptides in a dimer configuration to produce multivalent ligand target interactions to improve binding performance and allow for early targets to be detected at low levels of expression. We will use a flexible fiber multi-spectral endoscope that can pass through the working channel of a standard medical endoscope to detect multiple targets at the same time. Successful completion of these aims will provide an integrated multi-spectral imaging methodology to longitudinally visualize overexpressed molecular targets that drive progression of Barrett's esophagus to esophageal adenocarcinoma. This innovative approach can serve as the foundation for validated preventive measures to improve patient management.

- 项目摘要/摘要最近，食管（EAC）和胃食管连接（GEJAC）腺癌的发生率急剧增加，5年生存率低于15％。当发现这些手术后患者可以有良好的临床结果。这些观察结果强调了重要性早期癌症检测。众所周知，巴雷特食管（BE）患者的风险增加。我们的总体目标是推进成像的新方法以可视化空间分布的效果通过使用新型成像方法评估BE的遗传改变向EAC的进展。我们提出了一个多机构的，跨学科的，翻译研究中心巴雷特的食道翻译研究网络（BETRNET）。我们的使命是建立我们的专业知识在基因组表征，肽生物化学和临床翻译方面，以实现我们的最终目标在治疗干预措施最有效的早期阶段进行早期癌症检测。我们将识别一系列互补的基因，这些基因在细胞表面过表达，并将用于开发和验证新的肽成像剂。选择的目标将满足3个重要的临床需求： 1）实时内窥镜鉴定预防性病变和早期癌症以引导内窥镜检查切除; 2）为内窥镜监测时间安排的患者的风险分层； 3）检测胃没有内窥镜外观的患者的食管结腺瘤。我们将使用最先进的基因组工具来识别早期表达过度过表达的基因靶点通过提供基因表达改变，DNA副本的全面分析，将BE向EAC的进展数量变异和基因突变。我们将选择在细胞上表达的候选基因表面可以在体内进行内镜下成像。我们将严格验证候选人面板具有定量RT-PCR和免疫组织化学的靶标在组织微阵列上使用独立人类食管标本的队列。我们将使用这些目标首先识别和验证单体高度具体的肽。然后，我们将以二聚体配置排列单体肽以产生多价配体目标相互作用以提高结合性能并允许检测到早期目标在低水平的表达情况下。我们将使用柔性纤维多光谱内窥镜，可以通过标准医疗内窥镜的工作渠道同时检测多个靶标。这些目标的成功完成将为一个集成的多光谱成像方法提供纵向可视化过表达的分子靶标，这些靶标会驱动巴雷特食管的发展食管腺癌。这种创新的方法可以作为经过验证的预防性的基础改善患者管理的措施。