Clinical Investigation of Epigenetic Therapy

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The role of epigenetic transcriptional silencing of key tumor suppressor genes in many malignancies has been well established. The molecular mechanisms leading to this transcriptional silencing have begun to be lucidated over the last several years, leading to the concept that methylation of DNA interacts in a dynamic way with nuclear histones and Brg1- and hBrm-based SWI/SNF complexes to either repress or enhance transcription. Pre-clinical work in Chronic Lymphocytic Leukemia (CLL) has demonstrated these mechanisms of gene silencing are in fact clinically relevant, and that targeting more than one mechanism of gene silencing results in synergistic gene re-expression and concomitant apoptosis. Additional studies have demonstrated the ability of these agents to both activate alternative pathways of apoptosis not commonly utilized by chemotherapy or immunotherapy in CLL, and to up-regulate cell surface antigens that are potential molecular therapeutic targets. The overall hypothesis of this translational research Project is that application of epigenetic therapy targeting chromatin structure changes will relieve aberrant transcriptional repression of tumor suppressor genes, restore normal patterns of cell proliferation, differentiation and apoptosis, and ultimately result in clinical benefit to patients with CLL. The rational evaluation of these agents will require detailed study of the serial biologic effect of these agents in tumor samples and in vivo. As suggested by the reviewers, our research therefore will focus on CLL only. Our data support a detailed investigation of epigenetic therapy in CLL; furthermore, this disease provides the ability to isolate a large number of tumor cells from the blood at multiple points during treatment. The specific aims of this proposal are: 1) To perform a phase l/ll study of a novel schedule of depsipeptide combined with rituximab in patients with fludarabine-refractory CLL. This study will be accompanied by detailed mechanistic studies to assess the kinetics of histone deacetylase inhibition, targets modulated by histone deacetylase inhibition, and mechanisms of resistance to depsipeptide. 2) To perform a minimum effective pharmacologic dose-finding study of decitabine and then decitabine combined with valproic acid in fludarabine refractory CLL patients, followed by a randomized phase II study to determine the clinical and gene re-expression efficacy of these two therapeutic approaches. 3) To perform concurrent detailed pharmacologic and pharmacodynamic studies as part of the Aim 2 clinical trial. The development of each of these aims has been heavily dependent on the input of the basic science Projects, such as for the determination of target genes (particularly Projects 2 and 3), identification of histone modifications (Project 4), and importance of Brgland hBrm based SWI/SNF complexes (Project 5) in mediating the biologic effect of the epigenetically targeted therapies proposed herein. In addition, the findings derived from this translationally directed Project have already contributed to new hypotheses to be tested in the laboratory in Projects 2-5, as outlined in each of their proposals.