Clinical Investigation of Epigenetic Therapy

Ohio State University, Columbus OH

Investigators

Linked publications & trials

Abstract

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