Barrett's esophagus is a pre-malignant condition that predisposes to esophageal adenocarcinoma, which has one of the fastest rising incidence rates in the United States and has limited therapeutic options. THE LONG-TERM GOAL of our lab is to develop mechanism-based, safe chemopreventive agents to prevent carcinogenesis in Barrett's esophagus. The mechanisms of carcinogenesis in Barrett's esophagus is not completely understood but esophageal refluxate containing bile salts is implicated in this process. Bile salts can activate several cellular pathways including the NFKB survival pathway and cyclooxygenase-2 (COX-2) leading to high levels of prostaglandins in the esophagus. We have shown that certain prostaglandins, in particular PGE2, are associated with the development of neoplasia in Barrett's esophagus and their inhibition by COX-2 inhibitors results in prevention of esophageal cancer in an animal model of Barrett's esophagus. Human studies are underway to assess the chemopreventive effect of COX-2 inhibitors. Combinational chemoprevention, whereby synergism can be achieved between two chemopreventive agents, represents an important development in the field of cancer prevention. Ursodeoxycholic acid (Urso) is another potential chemopreventive agent, which is a tertiary bile salt with an established safety profile. It inhibits NFKB activation as well as phospholipase A2 both of which act upstream of COX-2 enzyme and can therefore be a novel combinational chemopreventive agent with COX-2 inhibitors. We recently observed that Urso increases apoptosis, inhibits cell proliferation and decreases PGE2 production in Barrett's epithelial cells as well as potentiates the effect of COX-2 inhibitors on these parameters. Urso also inhibits PGE2 production and reduces the concentration of carcinogenic bile salts in the duodenum of an animal model with esophageal reflux. Based on these observations, we propose the novel and mechanistic HYPOTHESIS that inhibition of carcinogenic bile salt mediated PGE2 production by Urso will compliment the chemopreventive action of COX-2 inhibitors in Barrett's esophagus via a negative regulation of NFKappaB activation. To test this hypothesis, we have two SPECIFIC AIMS. First we will assess the rate of adenocarcinoma and PGE2 levels in the esophagus with a combination of Urso + COX-2 inhibitor treatment and compare it to either Urso or COX-2 inhibitor treatment alone. Secondly, we will examine if a decline in the levels of activated NFkB in the esophagus results in decreased levels of PGE2 and decreased risk of adenocarcinoma in the esophagus and assess whether the association is explained by Urso and or COX-2 inhibitor treatment. We propose an in vivo study using an established model of Barrett's esophagus and adenocarcinoma. A successful outcome of this hypothesis-driven preclinical study will provide adequate information and rationale to initiate clinical trials involving the use of combinational Urso and COX-2 inhibitors in prevention of esophageal adenocarcinoma and to explore mechanistic steps involved in this process.
