Targeted Biochemoprevention in Barrett's Esophagus

描述（由申请人提供）：Barrett食管（BE）是一种癌前病变，正常的鳞状上皮被化生的特化上皮所取代。在这一人群中发生食管腺癌（EA）的风险很高，在过去的二十年中，美国BE和BE相关EA （BAA）的发病率迅速增加。目前尚无经证实的化学预防方法。我的长期目标是使用特定的分子靶点来设计BAA临床化学预防的转化方法。本应用的中心假设是，使用两种药物方案的积极化学预防干预可以优化疗效，同时最小化药物剂量和潜在毒性。在Specific Aim 1中，我们将研究CP461、表没食子儿茶素-3-没食子酸酯（EGCG）和白藜芦醇在三种人类baa来源的细胞系中的个体体外效应，包括它们抑制生长、诱导凋亡、阻滞细胞周期、改变细胞周期蛋白D1和环氧化酶-2 （cox-2）的细胞水平，以及抑制EGFR或erbB-2激活的能力。在特异性目标2中，我们将研究这些化合物在相同的三种细胞系中的添加剂和/或协同相互作用。将评估三种双药联合对生长抑制、凋亡诱导、细胞周期分布以及对cyclin D1、cox-2、EGFR磷酸化和erbB-2磷酸化表达的综合影响。根据这些效果，选择最“活跃”的组合进行临床评价。在Specific Aim 3中，我们将设计并开展一项具有生物学相关性的I期临床试点研究。在这项试验中，符合条件的BE患者将接受为期6个月的双药治疗方案。试验参与者将在试验开始时、试验结束时和停药6个月后接受标准的内窥镜检查和活检。将在这些时间间隔收集血清，以测量所给化合物的水平。毒性终点将是本试验的主要终点。活检标本将评估组织学变化、生物标志物表达和药物浓度。这个K23提案将在哥伦比亚大学进行，将帮助我在过渡到独立研究者期间发展我在癌症预防和治疗方面的转化研究项目。

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.