Principal Investigator

David
McCormick
Awardee Organization

IIT RESEARCH INSTITUTE
United States

Fiscal Year
2018
Project End Date

LFA-9 (mPGES-1/5-LOX Inhibitor): Preclinical Investigational New Drug (IND)-directed GLP Toxicology Studies

Familial Adenomatous Polyposis (FAP) is a rare inherited disease which results from an autosomal dominant genetic alteration in the adenomatous polyposis coli (APC) gene. Patients with this disease develop hundreds to thousands of pre-cancerous polyps (adenomas) in the duodenum, colon and rectum. Left untreated, patients have almost 100% lifetime risk of developing colorectal cancer (CRC). There is unequivocal evidence of chemopreventive efficacy in CRC with anti-inflammatory agents that exert their effects through COX-2 inhibition (e.g. aspirin, ibuprofen, naproxen and celecoxib), however chronic use of these agents is associated with an increased risk of GI toxicity. Moreover, agents that target COX-2 have been implicated in cardiovascular (CV) and thrombotic events for patients with a baseline history of atherosclerotic heart disease. Several investigators have shown the increased CV risk to be associated with reduced levels of prostaglandin I2 (PGI2 or prostacyclin) and increased levels of 5-lipoxygenase (5-LOX) metabolites. Hence, Dr. Rao and others hypothesize that agents that spare PGI2 and selectively block production of prostaglandin E-2 (PGE2) and 5-LOX metabolites should prove promising in the prevention of CRC. One such agent, licofelone, targets microsomal prostaglandin E Synthase-1 (mPGES-1) and 5-LOX, and suppresses small intestinal and colonic tumor formation in the ApcMin/+ mouse at doses that are devoid of overt toxicity. Inhibition of intestinal tumors was also associated with decreases in inflammatory cytokines and COX and 5-LOX activities. Furthermore, in clinical trials for osteoarthritis, the common side effects with licofelone were mild (abdominal pain and diarrhea). In silico molecular docking techniques and in vitro and in vivo screening methods have been employed to identify biologically active licofelone analogs. The lead candidate of this effort, LFA- 9, has been selected for further development. The main objective of this Task Order RFP is to conduct preclinical studies with LFA-9 to support its use in a clinical trial.