Targeting Histone Deacetylation: A Tool for Chemopevention of Esophageal Cancer

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DESCRIPTION (provided by applicant): Data supports that a newly developed phenylbutyrate-derived histone deacetylase inhibitor, S-HDACi-42, signficantly inhibits multiple cancer-associated processes in human esophageal adenocarcinoma cell lines, including increasing apoptosis, inhibiting cell proliferation, inducing a G2/M cell cycle arrest and significantly increasing expression of acetylated histones H3 and H4, and P21, P16 and the APC. Furthermore, our recent in vivo work supports that S-HDAC-42 is well tolerated at levels which alter histone acetylation status in the rat esophagus. Thus, our central hypothesis is that histone deacetylation is a molecular target for the prevention of esophageal cancer. Three objectives have been developed to address this hypothesis. First we propose to investigate the pharmacokinetics and pharmacodynamics of a newly developed histone deacetylase inhibitor, S-HDACi-42, in a clinically relevant rodent model of esophageal adenocarcinoma. A rat surgical model will be employed in which an esophagogastroduodenal anastomosis (EGDA) is performed to induce gastroesophageal reflux leading to the development of metaplastic columnar lined epithelium or Barrett's esophagus about 15 weeks post-surgery, and esophageal adenocarcinoma 40 weeks post-surgery. Second, we will investigate the potential of S-HDACi-42 to inhibit the development of esophageal adenocarcinoma and esophageal premalignancy. Third, this proposal seeks to identify modifications in histone proteins in the rat EGDA model and to elucidate the mechanisms by which S-HDACi-42 influences both epigenetic and nonepigenetic cancer associated processes in vivo. S-HDACi-42 will be evaluated as an anti-initiating and anti-promotion/progression agent. In summary, this project seeks to investigate a promising new approach, that of targeting the epigenome with a novel histone deacetylase inhibitor to prevent progression to esophageal adenocarcinoma. The five-year survival rate for those diagnosed with esophageal cancer is a dismal 14%, supporting the urgent need for improved preventive strategies. This study represents a necessary early step toward the long-term goal of identifying and translating efficacious preventive agents into the clinic for evaluation in high risk human cohorts, including patients with long standing Barrett's esophagus or