Targeting Histone Deacetylation: A Tool for Chemopevention of Esophageal Cancer

描述（由申请人提供）：数据支持新开发的苯基丁酸衍生的组蛋白去乙酰化酶抑制剂S-HDACi-42在人食管腺癌细胞系中显著抑制多种癌症相关过程，包括增加凋亡、抑制细胞增殖、诱导G2/M细胞周期阻滞和显著增加乙酰化组蛋白H3和H4、P21、P16和APC的表达。此外，我们最近的体内研究支持S-HDAC-42在改变大鼠食管组蛋白乙酰化状态的水平下具有良好的耐受性。因此，我们的中心假设是组蛋白去乙酰化是预防食管癌的分子靶点。为了解决这一假设，已经制定了三个目标。首先，我们建议研究新开发的组蛋白去乙酰化酶抑制剂s - hdac -42在食管腺癌临床相关啮齿动物模型中的药代动力学和药效学。采用大鼠手术模型，术后15周左右行食管胃十二指肠吻合（EGDA）诱导胃食管反流，形成化生的柱状上皮或Barrett食管，术后40周形成食管腺癌。其次，我们将研究s - hdac -42抑制食管腺癌和食管恶性前病变发展的潜力。第三，本研究旨在确定大鼠EGDA模型中组蛋白的修饰，并阐明s - hdac -42在体内影响表观遗传和非表观遗传癌症相关过程的机制。s - hdac -42将作为抗起始和抗促进/进展剂进行评估。总之，本项目旨在研究一种有前景的新方法，即用一种新的组蛋白去乙酰化酶抑制剂靶向表观基因组，以防止进展为食管腺癌。食管癌患者的5年生存率仅为14%，这表明迫切需要改进预防策略。这项研究为确定并将有效的预防药物转化为临床评估高风险人群（包括长期存在巴雷特食管或食管病变的患者）的长期目标迈出了必要的早期一步

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