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

摘要-本研究项目福尔斯的影响下，空间分布的遗传变异，在BE的 EAC的演变是RFA-CA-16-006中定义的领域之一。我们以前已经确定了EGFR和 ErbB 2基于高频基因扩增，使用基因表达谱作为细胞表面靶点， EAC的成像，并开发了对这些目标特异性的单体肽。我们现在的目标是发展 在项目1中确定的对从BE到EAC进展中出现的早期靶点具有特异性的新肽。 最近，我们已经鉴定了对早期靶标FGFR 2具有特异性的单体肽。因为遗传 驱动BE进展为EAC的事件可以发生在多个信号通路中，我们将开发一个 使用一组过表达的靶标来检测HGD和早期EAC患者的最大百分比。因为 预期早期靶点以低水平表达，我们将在二聚体中排列经验证的单体 在一些实施方案中，所述配体可以是多价构型，以产生多价配体-靶标相互作用，用于改善结合性能。这种效果是 用于抗体以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。更大的特异性可能是由于二聚体结合到更大的 与单体相比，目标表位的区域。我们将使用荧光团作为标签， 非重叠光谱，用于用柔性光纤多光谱内窥镜成像。仪器很小 足以通过标准医用内窥镜的工作通道，并可对粘膜成像 在真实的时间内测量远端食管的表面以引导组织活检。我们将进行“首次人体”临床 研究确定安全性，并为这种新型的综合成像方法提供早期疗效证据。 目标的成功完成将产生一组对早期靶点特异的单体肽， 在BE进展为EAC时出现，排列为二聚体，临床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.