The Role of Oxidative Stress in CLL B-cell Apoptosis

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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.