Colonic adenomas and adenocarcinomas arise as a direct result of stabilization of beta-catenin, often caused by the loss of function of the adenomatous polyposis coli (APC) gene. Indeed, it has been possible to reproduce the full spectrum of aberrant crypt foci, adenoma, carcinoma in mice through spontaneous or conditional mutations of APC, beta-catenin and SMAD4 (a key component of the TGF-beta signaling pathway) genes. Proteolytic enzymes play essential roles in tumor growth, angiogenesis, and invasion and optical in vivo imaging of key enzymes has recently been reported by us (Nature Med 2001; 7, 743-48). Specifically, we have shown that cathepsin B can be used as a highly sensitive imaging marker to detect inflammatory components in dysplastic adenomas (Gastroenterology, 2002; 122, 406- 14). The overall goal of this proposal is to extend our research to systematically explore the role of different cathepsins (D, B, L, K, S) and matrix metalloproteases (2, 7, 8, 9, 13) during colonic tumorigenesis. We hypothesize that some of these probes (e.g. cathepsin B) primarily report inflammation within a lesions, while others (e.g. MMP-7) report on genetically aberrant epithelium. Using mouse models we will screen and catalog lesional protease activities and compare imaging results to accepted gold standards. We subsequently will dissect the cellular components involved in protease production. As proof of principle we will then perform two clinically relevant studies in mouse models a) a screening study involving protease-imaging probes during colonoscopy and b) a study on imaging therapeutic efficacy of non-steroidal anti-inflammatory drugs in polyposis. These preclinical studies will prepare the grounds for near future clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA104547-02
Application #
6916429
Study Section
Gastrointestinal Cell and Molecular Biology Study Section (GCMB)
Program Officer
Knowlton, John R
Project Start
2004-07-01
Project End
2009-04-30
Budget Start
2005-07-01
Budget End
2006-04-30
Support Year
2
Fiscal Year
2005
Total Cost
$356,730
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Guo, Zhuyan; Dose, Marei; Kovalovsky, Damian et al. (2007) Beta-catenin stabilization stalls the transition from double-positive to single-positive stage and predisposes thymocytes to malignant transformation. Blood 109:5463-72
Khazaie, Khashayarsha; von Boehmer, Harald (2006) The impact of CD4+CD25+ Treg on tumor specific CD8+ T cell cytotoxicity and cancer. Semin Cancer Biol 16:124-36
Mempel, Thorsten R; Pittet, Mikael J; Khazaie, Khashayarsha et al. (2006) Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25:129-41

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