In vivo Detection of Neoplasia in the Digestive Tract.
Thomas D. Wang, M.D., Ph.D.
University of Michigan
Grant Number: U54CA136429
The University of Michigan has established an international, multi-disciplinary, multi-institutional Center in the Network for Translational Research (NTR) to develop standardize, validate, and optimize a targeted, multi-modal optical/nuclear imaging platform. This integrated imaging strategy uses labeled molecular probes to identify pre-malignant mucosa in the digestive tract for the early detection of cancer. This methodology has been developed to addresses an important unmet clinical need for improved detection of flat dysplasia that lacks architectural changes and goes undetected on surveillance endoscopy. Peptides are being developed for use as targeting agents because of their high diversity, small size, flexibility in labeling and minimal immunogenicity, and are well-suited for clinical use because of their rapid binding kinetics, deep tissue penetration and lack of toxicity.
The goal of the Primary Project is to establish the network infrastructure, standardize the imaging protocols and validate imaging performance. The detection of dysplasia with affinity peptides is performed in a systematic fashion. First, macroscopic imaging with PET/SPECT/CT localizes regions of disease in specific anatomic segments in the digestive tract with complete co-registration. Then, minimally invasive methods of mesoscopic imaging with fluorescence endoscopy are performed to directly visualize the spatial extent of the local targeted region over the large surface areas found in hollow organs. Finally, microscopic imaging with confocal techniques provides virtual histology to validate the pre-malignant lesions using quantitative criteria on optical sections.
We have combined the strengths and resources from academia, including the University of Michigan, Mayo Clinic, University of Washington, and VA Palo Alto, and industry, including Olympus Medical Systems Corp, GE Healthcare, Mauna Kea Technologies, and STI Medical Systems Inc, to establish a world class team of investigators to pursue these aims.
Phase 1 and 2 clinical studies will be performed to demonstrate the safety and efficacy of this novel, integrated imaging strategy. The results will then be used to plan a future multicenter clinical trial to begin at the end of the funding period. In addition, key needs in the Primary Project are being addressed by four Task-Specific Projects. The aims of the projects funded in year 1 include:
1) to develop radio-labeled peptides to localize dysplasia on PET/SPECT/CT in a CPC;APC mouse model of colon cancer;
2) to demonstrate vertical cross-sectional imaging with sub-mucosal tissue penetration depths using a miniature dual axes confocal microscope;
3) to select and validate peptides that affinity bind to high-grade dysplasia in Barrett's esophagus;
4) to develop a miniature scanning fiber endoscope for wide area surveillance in the bile and pancreatic ducts.