Colonoscopic Analysis of Response of Murine Colon Lesions to Drug Intervention

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DESCRIPTION (provided by applicant): Technological advancements in our ability to detect colorectal lesions early have failed to alter the status of colorectal cancer as the second leading cause of cancer-related deaths in the U.S. The sporadic nature of colorectal cancer, when combined with the lack of compliance of the general public with endoscopic surveillance guidelines, dictates the need to develop an efficacious chemopreventive regimen for this preventable disease. This group has recently succeeded in establishing reliable MRI and colonoscopic protocols for the reproducible image-based analysis of colon adenomas in vivo. Application of this new technology to our unique strain of Multiple Intestinal Neoplasia (Min) mice, which spontaneously develops multiple colon tumors, provides a novel opportunity to monitor the response of colon adenomas to chemopreventive intervention in vivo. Preliminary colonoscopic findings indicate that the Min model recapitulates the heterogeneous inhibitory response of colon adenomas to the nonsteroidal anti-inflammatory drug (NSAID) sulindac as seen in humans. The hypothesis of the proposed studies is that sulindac is more effective in inhibiting colon adenomas when administered in combination with the most frequently prescribed statin (cholesterol reducing agent), Atorvastatin (Lipitor). Colonoscopy and MRI will be used in Specific Aim 1 to monitor the response of colon adenomas to sulindac when given alone or in combination with Atorvastatin over time. Evaluable endpoints include changes in tumor growth rate, tumor latency, gross morphology and tumor incidence/multiplicity. Corresponding gene expression analyses of colon adenomas (Specific Aim 2) will provide insight into the level of expression of a battery of genes reported to be therapeutic targets of sulindac and Atorvastatin. Quantitative real-time PCR will be employed to compare the expression profile of: 1) colon adenomas from control and drug-treated animals and 2) subgroups of drug-responsive and -unresponsive lesions within each treatment group. The proposed studies represent the first application of small animal colonoscopy and MRI to an analysis of the response of individual colon tumors to drug therapy. The results of these novel studies are anticipated to contribute significantly to the future development of strategies to enhance the chemopreventive efficacy of NSAIDs against colon cancer by providing a comprehensive assessment of the underlying changes in gene expression responsible for associated alterations in gross morphology. These data could lead to the establishment of the first tolerable regimen for the chemoprevention of colorectal cancer. Public Health Relevance: By performing colonoscopies in the mouse, we are able to obtain information that we never had access to before regarding the responsiveness or unresponsiveness of independent colon tumors to drug treatment over time. Findings from this study could provide the basis for assessing the ability of nonsteroidal anti-inflammatory agents in combination with cholesterol-reducing agents to inhibit tumors in humans. These results could lead to the establishment of the first accepted therapy for the prevention of colon cancer.