Targeting Histone Deacetylation: A Tool for Chemopevention of Esophageal Cancer

描述(申请人提供)：资料支持新开发的苯丁酸组蛋白去乙酰酶抑制剂S-HDACi-42显著抑制人食管腺癌细胞系的多种癌症相关过程，包括增加细胞凋亡，抑制细胞增殖，诱导G2/M细胞周期停滞，显著增加乙酰化组蛋白H3和H4，P21，P16和APC的表达。此外，我们最近的体内工作支持S-HDAC-42在改变大鼠食管组蛋白乙酰化状态的水平上具有良好的耐受性。因此，我们的中心假设是组蛋白去乙酰化是预防食道癌的分子靶点。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酶抑制剂S-HDACi-42在临床相关的食管腺癌啮齿动物模型中的药代动力学和药效学。将采用大鼠手术模型，其中实施食管胃十二指肠吻合术(EGDA)以诱导胃食道反流，导致术后15周左右发生化生柱状衬里上皮或Barrett‘s食道，并在术后40周发生食管腺癌。其次，我们将研究S-HDACI-42对食管腺癌和食管癌前病变的抑制作用。第三，这项建议试图确定组蛋白蛋白在大鼠EGDA模型中的修饰，并阐明S-HDACi-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-HDACi-42将被评为抗引发剂和抗促进剂。综上所述，该项目试图探索一种有前景的新方法，即用一种新型的组蛋白脱乙酰酶抑制剂靶向表观基因组，以防止进展为食管腺癌。那些被诊断为食道癌的人的五年存活率是令人沮丧的14%，这支持了改进预防策略的迫切需要。这项研究是朝着确定有效预防药物并将其转化为临床以用于高危人群队列评估的长期目标迈出的必要的早期步骤，包括长期存在巴雷特食管炎或食管炎的患者。

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