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

-项目摘要/摘要 近年来，食道(EAC)和胃-食道交界处(GEJAC)腺癌的发病率 急剧增加，五年存活率不到15%。当及早发现时，这些 手术后患者可以获得良好的临床结果。这些观察结果强调了 早期癌症检测的能力。众所周知，Barrett‘s食道(BE)患者的风险增加。 我们的首要目标是提出新的成像方法来可视化空间分布的影响。 通过使用新的成像方法来评估肿瘤在BE上的异质性 向EAC进发。我们建议建立一个多机构、跨学科、翻译研究中心 巴雷特食道翻译研究网络(BETRNet)。我们的使命是在我们的专业知识基础上 在基因组特征、多肽生物化学和临床翻译方面，以实现我们的最终目标 在治疗干预最有效的早期阶段进行癌症早期检测。我们会 确定一组在细胞表面过度表达的互补基因，并用于 开发和验证新的多肽显像剂。选定的目标将满足3个重要的临床需求： 1)实时内窥镜识别癌前病变和早期癌症以指导内窥镜检查 切除；2)BE患者的风险分层以确定内窥镜监测的时机；以及3)检测胃肠道疾病。 食道结合部腺癌患者无BE的内窥镜表现。 我们将使用最先进的基因组工具来识别早期过度表达的基因靶点 通过提供基因表达变化、DNA复制的全面分析，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 在活体内可以通过内窥镜成像的表面。我们将严格验证候选人名单 组织微阵列定量RT-PCR和免疫组织化学检测靶点的研究 人类食道样本的队列。我们将首先使用这些靶标来鉴定和验证单体 具有高度特异性的多肽。然后我们将把单体多肽排列成二聚体构型，以产生 多价配体靶标相互作用，以提高结合性能并允许检测早期靶标 在低水平的表达下。我们将使用柔性光纤多光谱内窥镜，它可以穿过 标准医用内窥镜的工作通道，可同时检测多个目标。 这些目标的成功完成将提供一种综合的多光谱成像方法 纵向可视化高表达的分子靶点，驱动Barrett‘s食道进展到 食管腺癌。这一创新方法可以作为有效预防措施的基础 改善病人管理的措施。

- 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.