Grant Abstract: Targeted Chemoprevention of Flat and Polypoid Colitis-associated Dysplasias

Grant Number: 1R01CA183301-03S1
PI Name: Clapper
Project Title: Targeted Chemoprevention of Flat and Polypoid Colitis-associated Dysplasias

Abstract: This proposed administrative supplement to R01 CA183301 is being submitted in response to PA-16-319. Individuals with ulcerative colitis, a form of inflammatory bowel disease, face an increased risk of colorectal cancer and often develop folate deficiencies due to intestinal malabsorption or drug treatment. The proposed studies address a significant gap in our understanding of the benefits and risks associated with the use of folic acid supplements by this high-risk population.
Results from preliminary experiments conducted by this group demonstrate that administration of folic acid (0, 2 and 8 mg/kg diet) to mice with AOM/DSS–induced colitis for 16 weeks leads to a dose-dependent increase in the formation of colitis-associated neoplasia. This promotional effect of folic acid is accompanied by corresponding decreases in both the expression of IL-10 and the methylation of genes in pathways that are known to play a significant role in colon tumorigenesis. Although we have demonstrated that the morphological subtypes of colitis associated neoplasia (flat and polypoid) arise via distinct genetic mechanisms (subject of the Parent R01), folic acid caused the progression of both flat and polypoid dysplasias. Thus, folic acid appears to alter a pathway that is common to both types of lesions; one that could potentially serve as a target for preventive intervention.
The hypothesis of the proposed studies is that folic acid promotes the formation of colitis-associated colorectal tumors by modulating intra-colonic levels of cytokines and chemokines and inducing pro-oncogenic signaling pathways via changes in gene methylation. We propose to employ new cutting-edge technology to analyze samples of inflamed colorectal tissue that were banked previously from the chemopreventive assessment of folic acid in the AOM/DSS model. The impact of dietary folic acid (0, 2 and 8 mg/kg diet) on the expression of various cytokines and chemokines within the colon will be assessed in Aim 1 using state-of-the-art Luminex® xMap technology. Global genome-wide gene expression and methylation (DREAM) analyses will be employed in Aim 2 to identify genes that are differentially expressed and/or differentially methylated in the colitic colon (epithelial and stromal compartments). Subsequent analyses will reveal if the methylation status of the most differentially expressed genes is similar in flat and polypoid dysplasias following folic acid administration. Results from the proposed studies are anticipated to provide valuable insight into the mechanism by which folic acid promotes colitis-associated neoplasia and aid in identifying a molecular target for preventive intervention. The resulting data are also anticipated to inform guidelines for folic acid use by ulcerative colitis patients as well as the public in general, who through the fortification of foods and supplement use are ingesting folic acid at unprecedented levels.

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