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

摘要-本研究项目受BE基因改变的空间分布影响。 作为RFA-CA-16-006中定义的区域之一的EAC的演变。我们之前已经确定了EGFR和 基于高频基因扩增的ERBB2以基因表达谱为细胞表面靶点 EAC的成像，并已开发出针对这些靶点的单体多肽。我们现在的目标是开发 将在项目1中确定从BE到EAC过程中出现的针对早期靶点的新多肽。 最近，我们发现了一种针对早期靶标FGFR2的单体多肽。因为基因 推动BE向EAC进展的事件可能发生在多个信号通路中，我们将开发一种 检测HGD和早期EAC患者的最大百分比的过度表达靶点。因为 早期的靶标预计将在低水平表达，我们将以二聚体的形式安排有效的单体 用于产生多价配体-靶相互作用以提高结合性能的配置。这种效果是 被抗体用来实现非常高的结合亲和力和特异性。更高的敏感度可能发生在 同时检测两个独特的目标。从二聚体结合到更大的二聚体可能产生更大的特异性 将靶表位区域与单体表位区域进行比较。我们将使用荧光团作为标记，通过 柔性光纤多光谱内窥镜成像的非重叠光谱。这台仪器很小 足以穿过标准医用内窥镜的工作通道，并可以对粘膜进行成像 实时监测远端食道表面，指导组织活检。我们将进行“人类第一”临床试验 旨在为这种新颖的综合成像方法建立安全性并提供有效性的早期证据的研究。 成功完成AIMS将产生一组针对早期靶点的单体多肽， 出现在BE到EAC的进展中，以二聚体的形式排列，临床证明是安全的和早期的 有效的证据。

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.