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

- 项目总结/摘要 近年来，食管（EAC）和胃食管连接部（GEJAC）腺癌的发病率 急剧增加，5年生存率低于15%。如果及早发现， 患者在手术后可具有良好的临床结果。这些观察强调了 早期癌症检测。已知Barrett食管（BE）患者的风险增加。 我们的首要目标是推进新的成像方法，以可视化空间分布的影响 通过使用新的成像方法来评估BE中的遗传改变， 向EAC迈进。我们建议建立一个多机构，跨学科，翻译研究中心， Barrett食管转化研究网络（BETRNet）我们的使命是以我们的专业知识为基础 在基因组表征，肽生物化学和临床翻译，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早期癌症检测。我们将 鉴定在细胞表面过表达的互补基因组，并将用于 开发和验证新的肽显像剂。选择的目标将满足3个重要的临床需求： 1)实时内镜识别癌前病变和早期癌症，以指导内镜检查 切除术; 2）BE患者内镜监测时机的风险分层;以及3）胃- 内镜下无BE表现的食管连接部腺癌患者。 我们将使用最先进的基因组工具来鉴定在细胞中出现的早期过表达基因靶点。 通过提供基因表达改变、DNA拷贝、 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 它们可以在体内进行内窥镜成像的表面。我们将严格验证候选人小组 用定量RT-PCR和免疫组织化学在组织微阵列上检测靶点， 人食管样本队列。我们将使用这些目标首先识别和验证单体 高度特异性的肽。然后，我们将以二聚体构型排列单体肽， 多价配体靶相互作用，以改善结合性能并允许检测早期靶 低水平的表达。我们将使用一个灵活的光纤多光谱内窥镜，可以通过 标准医疗内窥镜的工作通道，以同时检测多个目标。 这些目标的成功实现将提供一种综合的多光谱成像方法， 纵向可视化过度表达的分子靶点，这些靶点推动巴雷特食管进展至 食管腺癌这种创新的方法可以作为有效的预防性治疗的基础。 改善病人管理。

- 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.