Barrett's Esophagus (BE) is a premalignant condition, in which the normal squamous epithelium is replaced by a metaplastic specialized epithelium. The risk of esophageal adenocarcinoma (EA) in this population is high, and during the past two decades, the incidence of both BE and BE-associated EA (BAA) in the United States has rapidly increased. No proven chemoprevention approaches in this disease exist. My long-range goal is to use specific molecular targets to design translational approaches to the clinical chemoprevention of BAA. The central hypothesis of this application is that an aggressive chemoprevention intervention using a two-drug regimen can optimize efficacy, while minimizing drug dosages and potential toxicities.
In Specific Aim 1, we will examine the individual in vitro effects of CP461, epigallocatechin-3-gallate (EGCG), and resveratrol in three human BAA-derived cell lines, with respect to their abilities to inhibit growth, induce apoptosis, arrest the cell cycle, alter cellular levels of cyclin D1 and cyclooxygenase-2 (cox-2), and inhibit either EGFR or erbB-2 activation.
In Specific Aim 2, we will investigate additive and/or synergistic interactions between these compounds in the same three cell lines. Three two-drug combinations will be evaluated for their combined effects on growth inhibition, apoptosis induction, cell cycle distribution, and on the expression of cyclin D1, cox-2, EGFR phosphorylation, and erbB-2 phosphorylation. Based on these effects, the most """"""""active"""""""" combination will be selected for clinical evaluation.
In Specific Aim 3, we will design and conduct a phase I clinical pilot study with biological correlates. In this trial, eligible patients with BE will receive a six-month treatment course using a two-compound regimen. Trial participants will undergo standard surveillance endoscopy and biopsy at trial entry, at trial completion, and after 6 months off-therapy. Serum will be collected at these intervals for measuring levels of the administered compounds. Toxicity endpoints will be the primary endpoints of this trial. Biopsy specimens will be evaluated for histologic changes, biomarker expression, and drug concentrations. This K23 proposal, which will take place at Columbia University, will help me to develop my translational research program in cancer prevention and therapy during my transition into an independent investigator.
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