Novel Molecular Target of Colon Cancer Chemoprevention by Polyethylene Glycol

Endeavor Health Clinical Operations, Evanston IL

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Abstract

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) ranks as the second leading cause of cancer deaths in the USA and thus highlighting the need for effective chemopreventive strategies. Several chemopreventive agents have shown promise in clinical studies;however, feasibility for population based CRC prevention has been hindered by insufficient efficacy or increased toxicity of number of these agents. Therefore, a safer and more potent agent is urgently needed. In this regard, work from a number of groups including ours, indicates that polyethylene glycol (PEG) is one of the most potent chemopreventive agents against both the azoxymethane (AOM)-treated rat and MIN mouse models of colon carcinogenesis. Moreover, PEG is widely used (over-the-counter) in clinical practice for the treatment of chronic constipation where it is remarkably safe. The critical issue for standardizing the effectiveness of a chemopreventive agent (nonsteroidals, etc) is the intra-individual variability. For PEG, the intra-individual variability may relate to its chemopreventive responsiveness as well as its effect on the bowel movement. The "normal'bowel habits of Americans range from 3 per day to 3 per week and PEG can dramatically influence these routines. Moreover, since bowel habits will effect mucosal contact time, this may affect chemopreventive response. Thus, it is clear that a single dose of PEG may not be effective in all patients and therefore, needs to be calibrated for individual requirements. It is critical to find a biomarker of PEG responsiveness that would be extremely dependable and easily accessible. Our laboratory has been interested in exploring the mechanism of action of PEG We demonstrated that PEG inhibited cellular proliferation in vivo in the premalignant mucosa of AOM-treated rat as well as in vitro in colon cancer cells. Increased cellular proliferation is an important premalignant cellular event that can be detected in the uninvolved mucosa distant from the site of developing neoplastic lesions (field effect). We have previously proposed a paradigm where PEG inhibits transcriptional repressor Snail (upregulated in CRC) with a concomitant induction of E-cadherin, inhibition of 2-catenin signaling (vital in early carcinogenesis) leading to PEG's anti-proliferative effects. Furthermore, we have noted (preliminary data) that PEG decreases the expression of epidermal growth factor receptor (EGFR), a critical proto-oncogene in early colon carcinogenesis and known to regulate Snail. We speculate that EGFR is the proximate membrane target for PEG effect. The importance of EGFR is underscored by our observation that in cell culture, knocking down EGFR via shRNA resulted in marked diminution of PEG responsiveness and its inability to downregulate Snail. We therefore, hypothesize that EGFR levels in the uninvolved mucosa will be an accurate biomarker for PEG-mediated chemoprevention of colon carcinogenesis. Furthermore, tailoring PEG dosage to EGFR levels will be an optimal approach. We contemplate that PEG will affect both facets of chemoprevention: prevention of initiation of lesions as well as regression of established premalignant lesions (adenomas).