The Role of Oxidative Stress in CLL B-cell Apoptosis

描述(申请人提供)：B-慢性淋巴细胞白血病(CLL)是美国最常见的白血病类型，目前是一种不治之症。以前的研究表明，CLL B细胞比正常淋巴细胞对氧化应激更敏感，这可能为本病患者提供一种潜在的选择性治疗策略。我们已经使用体外方法来鉴定利用CLL B细胞的这一生物脆弱性的药物，并特异性地鉴定了两种化合物，表没食子儿茶素没食子酸酯(EGCG)和Adaphostin，它们似乎至少部分地通过这种机制针对CLL B细胞。我们观察到EGCG和Adaphostin诱导氧化应激并选择性地杀伤CLL B细胞，这为测试这些药物在CLL患者中的临床疗效提供了强有力的理论基础。基于EGCG在人体中的良好毒性，我们现在开始每天口服EGCG治疗无症状早期CLL患者的L/11期临床试验，以确定我们的临床前观察是否可以转化为对这些患者的治疗益处。我们还将完成更多的研究，探索CLL B细胞对氧化应激的脆弱性的生物学基础，评估CLL B细胞-骨髓基质相互作用如何影响对ROS生成剂的敏感性，并探索将EGCG和其他ROS生成剂与其他用于治疗CLL的药物相结合的效果。这些研究将为未来的临床试验提供信息，探索如何将ROS生成剂与其他疗法结合起来，以优化疗效。为了实现这一目标，我们的具体目标是：目标1：进行一项临床试验，评估一种ROS生成剂EGCG治疗RAI状态0-II CLL患者的疗效。目的：进一步研究CLL B细胞对氧化应激易感性的生物学基础，评价CLL B细胞与骨髓基质的相互作用如何影响CLL B细胞对ROS生成剂的敏感性。目的：评价EGCG等ROS生成剂与其他治疗慢性淋巴细胞性白血病(CLL)常用药物联合应用时对CLL B细胞的影响。总的来说，这些研究旨在帮助开发一类具有独特作用机制(ROS生成)的药物，用于治疗CLL，以改善这种疾病患者的临床结果。这些研究将在职业发展计划的背景下进行，旨在为首席调查员作为临床试验人员的独立职业生涯做好准备。

DESCRIPTION (provided by applicant): B-Chronic Lymphocytic leukemia (CLL) is the most common type of leukemia in the U.S and is currently an incurable disease. Previous studies have demonstrated that CLL B-cells are more sensitive to oxidative stress than normal lymphocytes which may provide a potential selective therapeutic strategy for patients with this disease. We have used in vitro methods to identify agents that exploit this biologic vulnerability of CLL B-cells and have specifically identified two compounds, epigallocatechin gallate (EGCG) and adaphostin that appear to target CLL B-cells at least in part through this mechanism. Our observations that EGCG and adaphostin induce oxidative stress and selectively kill CLL B-cells, provides a strong rationale for testing the clinical efficacy of these agents in patients with CLL. Based on the favorable toxicity profile of EGCG in human subjects, we are now opening a phase l/ll clinical trial of daily oral EGCG for treatment of patients with asymptomatic, early stage CLL to determine if our preclinical observations can translate into therapeutic benefit for these patients. We will also complete additional studies that explore the biologic basis of CLL B-cells vulnerability to oxidative stress, assess how CLL B-cell - marrow stroma interactions affect sensitivity to ROS generating agents, and explore the effect of combining EGCG and other ROS generating agents with other agents used to treat CLL. These studies will inform future clinical trials exploring how to combine ROS generating agents with other therapies to optimize efficacy. To accomplish this our Specific Aims are: Aim 1: Conduct a clinical trial evaluating the efficacy of one ROS generating agent, EGCG, for treatment of patients with Rai state 0-II CLL. Aim 2: Further investigate the biologic basis for CLL B-cell vulnerability to oxidative stress and evaluate how CLL B-cell - marrow stromal interactions affect the sensitivity of CLL B-cells to ROS generating agents. Aim 3: Evaluate the effect of EGCG and other ROS generating agents on CLL B-cells when combined with other agents commonly used for treatment of patients with CLL. Collectively, these studies are designed to help develop a category of agents with a unique mechanism of action (ROS generation) for treatment of CLL to improve clinical outcomes for patients with, this disease. These studies will be conducted within the context of a career development plan aimed at preparing the principle investigator for an independent career as a clinical trialist.