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

项目 2：用于从 BE 到 EAC 进展的早期靶点的肽显像剂

• 批准号: 10155439
• 负责人: Thomas D Wang
• 金额: $ 31.68万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-21 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155439
• 关键词: Affinity; Antibodies; Appearance; Architecture; Area; Barrett Esophagus; Barrett' s neoplasia; Binding; Biodistribution; Biological; Biology; Biopsy; Cell surface; Clinical; Clinical Research; Detection; Diagnostic; Diagnostic Procedure; Distal; ERBB2 gene; Endoscopes; Endoscopy; Epidermal Growth Factor Receptor; Epitopes; Esophageal Adenocarcinoma; Esophagus; Event; Evolution; Extracellular Domain; FGFR2 gene; Fiber; Foundations; Gene Amplification; Gene Expression; Gene Frequency; Genetic; Healthcare; Human; Image; Incidence; Intervention; Label; Lead; Lesion; Ligands; Light; Malignant Neoplasms; Maps; Medical; Methods; Molecular; Mucous Membrane; Mutation; Patients; Peptides; Performance; Phage Display; Preventive measure; Property; Research; Research Project Grants; Risk; Safety; Screening for cancer; Signal Pathway; Small Interfering RNA; Societies; Spatial Distribution; Specificity; Surface; Time; Tissues; Topical application; Toxic effect; Validation; base; care burden; chromoscopy; contrast imaging; cost; dimer; falls; first-in-human; flexibility; fluorophore; imaging agent; imaging approach; improved; in vivo; in vivo imaging; insight; instrument; knock-down; minimal risk; monomer; novel; overexpression; prevent; recruit; stomach cardia; targeted agent; targeted delivery; targeted imaging; tool

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.

摘要 - 该研究项目属于遗传改变的空间分布在BE上的影响 EAC作为RFA-CA-16-006中定义的区域之一的演变。我们以前已经确定了EGFR和 基于高频基因扩增的ERBB2，使用基因表达谱作为细胞表面靶标 EAC的成像，并开发了针对这些靶标的特定于这些靶标的单体。我们现在旨在发展 针对从BE到EAC的早期靶标特有的新肽在项目1中鉴定出来。 最近，我们确定了一种针对早期靶标FGFR2的单体肽。因为遗传 可以在多个信号通路中发生驱动BE向EAC的事件发生，我们将开发一个 过表达目标的面板可检测HGD和EAC早期患者的最大百分比。因为 预计早期目标将以低级别表示，我们将在二聚体中安排经过验证的单体 配置可产生多价配体 - 靶标相互作用，以改善结合性能。这种效果是 抗体用于实现非常高的结合亲和力和特异性。从 简单检测两个独特的目标。二聚体与较大的二聚体可能产生更大的特异性 与月相比，目标表位区域的区域。我们将使用荧光团作为发出的标签 具有柔性纤维多光谱内窥镜成像成像的非重叠光谱。乐器很小 足以通过标准医疗内窥镜的工作渠道，并可以对粘膜进行成像 实时的食管远端表面引导组织活检。我们将执行“人类第一”临床 为建立安全性并为这种新颖的综合成像方法提供效率的早期证据。 成功完成目标将导致一个单体小组针对早期目标的特定于 出现在BE向EAC的进展中，该EAC被排列为二聚体，并在临床上证明了安全性和早期 效率的证据。