Targeted Biochemoprevention in Barrett's Esophagus

描述（由申请方提供）：Barrett食管（BE）是一种癌前病变，其中正常鳞状上皮被化生特化上皮取代。 该人群中食管腺癌（EA）的风险较高，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。 目前尚无已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。 本申请的中心假设是使用双药物方案的积极化学预防干预可以优化功效，同时最小化药物剂量和潜在毒性。 在具体目标1中，我们将研究CP 461，表没食子儿茶素-3-没食子酸酯（EGCG），白藜芦醇在三个人BAA衍生细胞系中的体外作用，就其抑制生长，诱导凋亡，阻止细胞周期，改变细胞周期蛋白D1和环氧合酶-2（考克斯-2）的细胞水平，以及抑制EGFR或erbB-2活化的能力而言。 在具体目标2中，我们将研究这些化合物在相同的三种细胞系中的相加和/或协同相互作用。 将评价三种两药组合对生长抑制、细胞凋亡诱导、细胞周期分布以及对细胞周期蛋白D1、考克斯-2、EGFR磷酸化和erbB-2磷酸化表达的联合作用。 基于这些效应，将选择最“活性”的组合进行临床评价。 在具体目标3中，我们将设计并进行一项具有生物学相关性的I期临床试点研究。 在本试验中，符合条件的BE患者将接受为期6个月的双化合物方案治疗。 试验受试者将在试验入组时、试验完成时和停止治疗6个月后接受标准监测内镜检查和活检。 将在这些时间间隔采集血清，用于测量给药化合物的水平。 毒性终点将是本试验的主要终点。 将评价活检标本的组织学变化、生物标志物表达和药物浓度。 这个K23的建议，这将发生在哥伦比亚大学，将帮助我发展我的癌症预防和治疗的转化研究计划，在我过渡到一个独立的研究者。

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.