Chemoprevention of Colitis-Associated Neoplasia by 5-ASA

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DESCRIPTION (provided by applicant): Although ulcerative colitis patients are at a significantly increased risk of developing colorectal cancer as compared to the general population, little attention has been given to the development of a chemopreventive intervention for this high-risk population. Furthermore, colonoscopies fail to reliably detect early lesions, in particular flat dysplasias, in ulcerative colitis patients. Rationale for the proposed study is provided by preliminary data from this group that demonstrate the ability of 5-aminosalicylic acid (5-ASA), the first-line therapy for the treatment of human colitis, to inhibit the multiplicity of AOM/DSS-induced colitis-associated dysplasias in mice when given prior to the induction of colitis. Most interesting was the potential differential response of polypoid (reduction in size) and flat (decrease in multiplicity) dysplasias to drug therapy. These data suggest that flat and polypoid dysplasias may respond differently to 5-ASA exposure and that these lesion subtypes may arise via independent genetic pathways. More recent data from this group confirm that 5-ASA can inhibit colitis-associated lesions when administered after the induction of DSS; a schedule of clinical relevance. The overall goal of this study is to gain new insight into the chemopreventive activity of 5-ASA against AOM/DSS-induced colitis-associated colorectal cancer by combining novel imaging techniques with state- of-the-art advances in genetic profiling and bioinformatics. The hypothesis of the proposed experimentation is that 5-ASA effectively inhibits colitis-associated neoplasia by altering the growth of polypoid and flat lesions via distinct genetic pathways. The ability of an optimal dose of 5-ASA to decrease the multiplicity and size of colonic dyplasias as well as associated inflammation will be examined in Specific Aim 1. These data will be complemented by the use of MRI, colonoscopy and whole-body fluorescence imaging with biologically activated probes to monitor both the degree of inflammation (colon wall thickness) and the growth of polypoid and flat lesions over time. In Specific Aim 3, microarray-based analyses will be employed to compare and contrast the gene expression profile of inflamed nonneoplastic mucosa with that of polypoid and flat dysplasias as well as to identify those genes whose expression is altered in each tissue type following exposure to 5-ASA. Findings from these preclinical analyses are anticipated to enhance our understanding of the genetic basis of polypoid and flat colitis-associated dysplasias and facilitate the development of a chemopreventive regimen for ulcerative colitis patients at increased risk for colonic malignancies. PUBLIC HEALTH RELEVANCE: Because colonoscopies do not reliably detect early colon cancer in ulcerative colitis patients, there is a great need to develop a cancer preventive therapy for this high-risk population. Findings from the proposed mouse studies could lead to the use of 5-ASA for cancer prevention and significantly impact the establishment of future guidelines for the clinical management of patients with inflammatory bowel disease.