Project 2: Peptide imaging agents for early targets in progression from BE to EAC

摘要 – 该研究项目属于 BE 遗传改变空间分布对 EAC 作为 RFA-CA-16-006 中定义的领域之一的演变。我们之前已经鉴定出 EGFR 和 ErbB2 基于高频基因扩增，使用基因表达谱作为细胞表面靶标 EAC 成像并开发了针对这些目标的单体肽。我们现在的目标是发展 项目 1 中将鉴定针对从 BE 到 EAC 进展过程中出现的早期靶点的新肽。 最近，我们鉴定了一种对早期靶点 FGFR2 具有特异性的单体肽。因为遗传 驱动BE进展为EAC的事件可能发生在多种信号通路中，我们将开发一个 一组过表达的靶标可检测最大比例的 HGD 和早期 EAC 患者。因为 早期目标预计会以低水平表达，我们将在二聚体中排列经过验证的单体 配置产生多价配体-靶标相互作用以提高结合性能。这个效果是 抗体使用它来实现非常高的结合亲和力和特异性。更高的灵敏度可以发生在 同时检测两个独特的目标。二聚体与更大的结合可能会产生更大的特异性 目标表位区域与单体区域的比较。我们将使用荧光团作为发射的标签 使用柔性光纤多光谱内窥镜进行成像的非重叠光谱。仪器体积小 足以通过标准医用内窥镜的工作通道，并对粘膜进行成像 实时监测远端食管表面组织活检。我们将进行“首次人体”临床 研究旨在确定这种新颖的综合成像方法的安全性并提供有效性的早期证据。 成功完成这些目标将产生一组针对早期目标的单体肽， 在 BE 发展为 EAC 的过程中出现，其排列为二聚体，临床已证明其安全性和早期 功效的证据。

Abstract – This research project falls under effects of spatial distribution of genetic alterations in BE on the evolution of EAC as one of the areas defined in RFA-CA-16-006. We have previously identified EGFR and ErbB2 based on high-frequency gene amplification using gene expression profiles as cell surface targets for imaging of EAC and have developed monomer peptides specific for these targets. We now aim to develop new peptides specific for early targets that arise in progression from BE to EAC to be identified in Project 1. Recently, we have identified a monomer peptide that is specific for the early target FGFR2. Because genetic events that drive progression of BE to EAC can be occur in multiple signaling pathways, we will develop a panel of overexpressed targets to detect the largest percentage of patients with HGD and early EAC. Because early targets are expected to be expressed at low levels, we will arrange validated monomers in a dimer configuration to produce multivalent ligand-target interactions for improving binding performance. This effect is used by antibodies to achieve very high binding affinity and specificity. Higher sensitivity can occur from simultaneous detection of two unique targets. Greater specificity may arise from dimer binding to larger regions of target epitope compared with that of monomer. We will use fluorophores as labels that emit with non-overlapping spectra for imaging with a flexible fiber multi-spectral endoscope. The instrument is small enough to pass through the working channel of a standard medical endoscope, and can image the mucosal surface of the distal esophagus in real time to guide tissue biopsy. We will perform “first-in-human” clinical studies to establish safety and provide early evidence of efficacy for this novel, integrated imaging approach. Successful completion of the aims will result in a panel of monomer peptides specific for early targets that arise in progression of BE to EAC that are arranged as dimers and clinical demonstrated for safety and early evidence of efficacy.