Prevention and Therapy of Inflammation Associated Colorectal Cancer

This application is focused on the synthesis and development of MTDIA, a novel transition state inhibitor of MTAP (5'-methylthioadenosine phosphorylase) in the S-adenosylmethionine (SAM) salvage pathway, and our recently synthesized MTDIA pro-drugs with improved pharmacodynamics. This was based on solving the transition state structure of MTAP. Our data and reports in the literature strongly support the hypothesis that targeting MTAP with MTDIA or the prodrugs will be especially effective in preventing and/or treating inflammation linked tumors. This will be investigated in 2 novel mouse models we have developed of: 1) sporadic colon tumors, the most common form of the disease; 2) rectal tumors. The potential that MTDIA can be effective in prevention as well as treatment is established by: 1) absence of detectable toxicity at a dose more than 30-fold higher than the optimal dose inhibiting tumor growth; 2) data that aggressive treatment for early remission of inflammation in human inflammatory bowel disease can mitigate longer-term effects, including tumor development. MTDIA and the prodrugs target the unique transition state structure of MTAP. Therefore, the drugs have extraordinary specificity and efficacy. We have established efficacy of MTDIA in inhibition of tumor growth in ApcMin/+ mice, a human Pdx tumor, a human colon tumor organoid model, and in multiple human tumor cell lines. Aim1 will determine efficacy of MTDIA, and prodrugs with improved pharmacodynamics, for prevention and/or treatment of tumors and effect on inflammatory infiltrates in: a) our unique, well-documented, dietary model of mouse sporadic colon tumorigenesis driven by inflammation 12,16-24; b) the Muc2 genetic knockout mouse we constructed in which loss of the mucus barrier causes chronic inflammation and that as a consequence, is a unique model of rectal cancer in the mouse 25, 26-29 30,31. Effects of the drugs on tumor incidence, size and histopathology will be determined. Aim 2: determines the effect of MTDIA and the prodrugs on: a) elevating MTA, the substrate of MTAP identified as a key in mitigating IBD; b) inflammation; c) based on published and preliminary data, apoptosis and altered stem cell programming as mechanisms by which MTDIA and prodrugs target tumor inhibition in these unique models.