Efficacy of an Electrophile Scavenger in the Prevention of Gastrointestinal Inflammatory Carcinogenesis

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SUMMARY: Many cancers are recognized to have an inflammatory etiology. Gastric cancer, the third leading cause of cancer deaths worldwide, is the prototype- it is caused by infection with the bacterial pathogen Helicobacter pylori in 90% of cases. For colorectal cancer (CRC), the second leading cause of cancer deaths, inflammatory bowel disease (IBD) is a frequent precursor lesion. This STTR Phase I proposal is a partnership between the Wilson Lab at Vanderbilt University Medical Center (VUMC), which is focused on gastrointestinal inflammation- associated carcinogenesis, and MTI BioTech, Inc. (MTI), who are together developing a new therapeutic strategy to prevent cancer. Under conditions of chronic mucosal inflammation, increased enzyme activities result in formation of dicarbonyl electrophiles, products of lipid peroxidation that include isolevuglandins (isoLGs), malondialdehyde, 4-oxo-nonenal, and acrolein, all of which can form adducts with DNA, histones, and proteins. This adduct formation may lead to somatic genomic abnormalities and risk for neoplastic transformation. The compound 2-hydroxybenzylamine (2-HOBA) can serve as a scavenger of all electrophiles, thus preventing adduct formation. 2-HOBA is a natural product derived from buckwheat seeds. It has been shown to be highly bioavailable, with no toxicity, in rodents and in recent human Phase I clinical trials. 2-HOBA protects mice from oxidative damage in models of hypertension and Alzheimer’s disease. The Wilson Lab has discovered that isoLG adducts are increased i) in gastric tissues of patients and mice infected with H. pylori; ii) in the colon of humans with chronic colitis from inflammatory bowel disease, and colitis-associated cancer (CAC), and mice treated with azoxymethane-dextran sulfate sodium (AOM-DSS), a model of CAC. The Lab has found that a 2-HOBA analog, EtHOBA, which also scavenges electrophiles, markedly reduces gastric dysplasia and carcinoma in two models of H. pylori-induced gastric carcinoma, transgenic FVB/N insulin-gastrin (INS-GAS) mice and Mongolian gerbils, and reduces colonic tumorigenesis in the AOM-DSS CAC model. However, unlike 2-HOBA, EtHOBA has not reached development for human use. We hypothesize that electrophiles have a key role in inflammation-driven gastrointestinal carcinogenesis via formation of adducts to macromolecules and are new molecular targets for cancer prevention by 2-HOBA. We will determine the protective effect of 2-HOBA on H. pylori-induced gastric carcinogenesis in INS-GAS mice and gerbils (Aim 1) and on colitis-associated carcinogenesis in the AOM-DSS mouse model (Aim 2). Primary endpoints will be reduction in dysplasia, carcinoma, and tumor formation, and secondary endpoints will be effects on DNA damage and isoLG adducts. A successful STTR Phase I outcome will be a protective effect of 2-HOBA on gastric and colon carcinogenesis and will be the primary go/no go endpoint to a Phase II STTR project. We envision future studies testing 2-HOBA in animals in which disease is already fully established; further assessment of molecular mechanisms underlying protective effects, including in human organoids; and human clinical trials in patients with precancerous gastric and colon lesions.