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

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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.