Targeted Biochemoprevention in Barrett's Esophagus

描述(申请人提供)：巴雷特食道(BE)是一种癌前状态，正常的鳞状上皮被化生的特化上皮所取代。食管腺癌(EA)的风险很高，在过去的二十年里，BE和BE相关的EA(BAA)在美国的发病率迅速上升。在这种疾病中，还没有经过验证的化学预防方法。我的长期目标是使用特定的分子靶点来设计翻译方法来预防BAA的临床化学预防。这一应用的中心假设是，使用两种药物方案的积极化学预防干预可以优化疗效，同时将药物剂量和潜在毒性降至最低。在具体目标1中，我们将考察CP461、表没食子儿茶素没食子酸酯(EGCG)和白藜芦醇对三种人BAA来源的细胞株的体外作用，观察它们抑制生长、诱导细胞凋亡、阻止细胞周期、改变细胞周期蛋白D1和环氧合酶-2(COX-2)水平以及抑制EGFR或erbB-2激活的能力。在特定的目标2中，我们将在相同的三个细胞系中研究这些化合物之间的相加和/或协同作用。将评估三种两药组合在抑制生长、诱导细胞凋亡、细胞周期分布以及对Cyclin D1、COX-2、EGFR磷酸化和erbB-2磷酸化的表达方面的联合作用。根据这些效果，将选择最“活跃”的组合进行临床评估。在具体目标3中，我们将设计并进行一项具有生物相关性的I期临床先导研究。在这项试验中，符合条件的BE患者将接受为期6个月的治疗，使用两种复合方案。试验参与者将在试验开始时、试验结束时和停药6个月后接受标准的监视内窥镜检查和活检。将在这些时间间隔收集血清，以测量所用化合物的水平。毒性终点将是这项试验的主要终点。将评估活检标本的组织学变化、生物标记物的表达和药物浓度。这项K23计划将在哥伦比亚大学进行，它将帮助我在过渡到独立研究员的过程中发展我的癌症预防和治疗方面的转化研究计划。

DESCRIPTION (provided by applicant): 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.