Over the past 3 decades, the incidence of esophageal adenocarcinoma (EAC) has risen faster than any other cancer in developed countries, a trend that is expected to continue with increasing prevalence of obesity and acid reflux. This disease is believed to arise from Barrett's esophagus, where early cancer detection is currently performed on white light endoscopy with random biopsies. This approach is prone to sampling error because high-grade dysplasia (HGD) and early EAC are difficult to detect on imaging because of flat morphology, patchy distribution, and low prevalence. The genes for epithelial growth factor receptors, EGFR and ErbB2, are amplified in high frequency in EAC with minimal overlap among individual patients. The corresponding protein targets are expressed on the cell surface and accessible to in vivo imaging with use of highly specific peptides. We will develop a multimer that links individual peptides specific for either EGFR or ErbB2, and attach Cy5.5, a bright near-infrared (NIR) fluorophore for imaging. We will optimize the peptides on alignment to these targets using a structural model, and validate specific binding on competition and siRNA knockdown studies. We will characterize binding affinity and rapid binding on flow cytometry, and validate binding of the optimized multimer on human specimens of esophageal neoplasia ex vivo using a multi-modal NIR endoscope. Fluorescence and reflectance images will be ratioed to correct for difference in distance and geometry over the image field-of-view. The threshold that maximizes variance will be used to create a binary image. The contour will define a red-flag region on the white light image to help physicians guide tissue resection. These experiments will verify instrument sensitivity to target overexpression. We will then perform a pharmacology toxicology study in animals to establish multimer safety, and submit an Investigational New Drug Application (IND) to the FDA to perform a first-in-human clinical study. The multimer will first be evaluated in patients to establish safety and then studied on imaging to validate binding to early neoplasia. The results will be compared with histology. Successful completion of these aims will provide the medical community with an integrated multi modal imaging methodology that detects overexpressed cell surface targets to guide tissue resection of lesions that have increased risk for progressing onto cancer, detect cancer at the earliest stages possible, reduce overdiagnosis, and distinguish lethal from non-lethal disease. This collaborative work will be performed by a multi-disciplinary team at the University of Michigan, including TD Wang who will develop the peptide multimer, DG Beer who will validate specific multimer binding to EGFR and ErbB2, and DK Turgeon who will perform the clinical studies. This experienced team has recently completed an FDA-approved first-in-human imaging study of a monomer peptide in esophagus.
The incidence of esophageal cancer has risen faster than any other cancer in developed countries. Early lesions are difficult to detect on conventional white light endoscopy because they are flat in appearance, patchy in distribution, and low in prevalence. Cancer biomarkers can be developed to detect this disease on imaging before mass lesions appear to improve methods for early cancer detection.
|Chen, Jing; Gao, Zhenghong; Li, Gaoming et al. (2018) Dual-modal in vivo fluorescence and photoacoustic imaging using a heterodimeric peptide. Chem Commun (Camb) 54:13196-13199|
|Joshi, Bishnu P; Wang, Thomas D (2018) Targeted Optical Imaging Agents in Cancer: Focus on Clinical Applications. Contrast Media Mol Imaging 2018:2015237|
|Zhou, Juan; He, Lei; Pang, Zhijun et al. (2017) Identification and validation of FGFR2 peptide for detection of early Barrett's neoplasia. Oncotarget 8:87095-87106|
|Gao, Zhenghong; Li, Gaoming; Li, Xue et al. (2017) In vivo near-infrared imaging of ErbB2 expressing breast tumors with dual-axes confocal endomicroscopy using a targeted peptide. Sci Rep 7:14404|
|Joshi, Bishnu P; Duan, Xiyu; Kwon, Richard S et al. (2016) Multimodal endoscope can quantify wide-field fluorescence detection of Barrett's neoplasia. Endoscopy 48:A1-A13|
|Joshi, Bishnu P; Zhou, Juan; Pant, Asha et al. (2016) Design and Synthesis of Near-Infrared Peptide for in Vivo Molecular Imaging of HER2. Bioconjug Chem 27:481-94|
|Zhou, Quan; Li, Zhao; Zhou, Juan et al. (2016) In vivo photoacoustic tomography of EGFR overexpressed in hepatocellular carcinoma mouse xenograft. Photoacoustics 4:43-54|
|Joshi, Bishnu P; Wang, Thomas D (2016) Gastrointestinal imaging in 2015: Emerging trends in endoscopic imaging. Nat Rev Gastroenterol Hepatol 13:72-3|
|Joshi, Bishnu P; Pant, Asha; Duan, Xiyu et al. (2016) Multimodal Video Colonoscope for Targeted Wide-Field Detection of Nonpolypoid Colorectal Neoplasia. Gastroenterology 150:1084-1086|
|Zhou, Juan; Joshi, Bishnu P; Duan, Xiyu et al. (2015) EGFR Overexpressed in Colonic Neoplasia Can be Detected on Wide-Field Endoscopic Imaging. Clin Transl Gastroenterol 6:e101|