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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Subcommittee G - Education (NCI)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
United States
Zip Code
Byrd, John C; Furman, Richard R; Coutre, Steven E et al. (2015) Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125:2497-506
Lucas, David M; Ruppert, Amy S; Lozanski, Gerard et al. (2015) Cytogenetic prioritization with inclusion of molecular markers predicts outcome in previously untreated patients with chronic lymphocytic leukemia treated with fludarabine or fludarabine plus cyclophosphamide: a long-term follow-up study of the US intergr Leuk Lymphoma 56:3031-7
Blachly, James S; Ruppert, Amy S; Zhao, Weiqiang et al. (2015) Immunoglobulin transcript sequence and somatic hypermutation computation from unselected RNA-seq reads in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A 112:4322-7
Flynn, J; Jones, J; Johnson, A J et al. (2015) Dinaciclib is a novel cyclin-dependent kinase inhibitor with significant clinical activity in relapsed and refractory chronic lymphocytic leukemia. Leukemia 29:1524-9
Motiwala, T; Kutay, H; Zanesi, N et al. (2015) PTPROt-mediated regulation of p53/Foxm1 suppresses leukemic phenotype in a CLL mouse model. Leukemia 29:1350-9
Claus, Rainer; Lucas, David M; Ruppert, Amy S et al. (2014) Validation of ZAP-70 methylation and its relative significance in predicting outcome in chronic lymphocytic leukemia. Blood 124:42-8
Dong, Shuai; Guinn, Daphne; Dubovsky, Jason A et al. (2014) IPI-145 antagonizes intrinsic and extrinsic survival signals in chronic lymphocytic leukemia cells. Blood 124:3583-6
Kohrt, Holbrook E; Sagiv-Barfi, Idit; Rafiq, Sarwish et al. (2014) Ibrutinib antagonizes rituximab-dependent NK cell-mediated cytotoxicity. Blood 123:1957-60
Wei, Quan-Xiang; Claus, Rainer; Hielscher, Thomas et al. (2013) Germline allele-specific expression of DAPK1 in chronic lymphocytic leukemia. PLoS One 8:e55261
Singh, Rajbir; Mortazavi, Amir; Telu, Kelly H et al. (2013) Increasing the complexity of chromatin: functionally distinct roles for replication-dependent histone H2A isoforms in cell proliferation and carcinogenesis. Nucleic Acids Res 41:9284-95

Showing the most recent 10 out of 73 publications