Project 1: Early Predisposing Genes and Risk Stratification for CLL

Project Leaders: Albert de la Chapelle, MD, PhD, and John Byrd, MD

Project 1 focuses on the identification and investigation of early predisposition factors in CLL. The first aim of this project extends findings from a co-authored paper published in the journal Cell in which DAPK1 silencing was shown to associate with development of CLL in a family with a high frequency of this disease. This aim investigates the function of DAPK1 in B-cells and studies in depth the leukemogenic role for DAPK1 silencing in CLL. It is expected that the work derived from the study of DAPK1 will lead to identification of new biomarkers to predict CLL outcome in Aim 2, and potentially innovative treatments with novel compounds that could be designed by investigators in Core D. The second aim examines the clinical relevance of promoter methylation of initiating (DAPK1, FOXD3) or progression (ID4) genes, expression of initiating genes (TCL1A) and other molecular markers (global hypomethylation) with disease progression and clonal evolution. Together, the two specific aims of this project will provide a significantly better understanding of early events in CLL transformation and, concomitantly, improve strategies to risk-stratify and treat lgVH unmutated CLL.

Project 2: Molecular Characterization and Risk Stratification of Acute Myeloid Leukemia

Project Leaders: Clara D. Bloomfield, MD

Project 2 focuses on epigenetic, microRNA, and gene expression profiling to predict treatment outcome and specific patient groups that will best benefit from targeted therapy in acute myeloid leukemia (AML). Drs. Bloomfield and Marcucci have a long record of using cytogenetic, molecular and, now, whole genomic profiling to perform risk-stratified (choosing therapy based upon molecular marker) treatment of AML. Their work with other members of this Leukemia SPORE has led to assigning specific therapy based upon cytogenetic or molecular markers. A recent example of this work on mRNA and miR profiling was published in The New England Journal of Medicinie. In this study, integrated prognostic signatures could be associated to leukemia-relevant pathways that are potentially subject to intervention using specific targeted therapies. In this proposal, these two senior investigators will focus on examining novel molecular markers, multi-gene expression signatures, and multi-microRNA expression signatures in the context of newly diagnosed AML patients enrolled on CALGB clinical trials to facilitate risk-stratified and molecular marker-stratified treatment. Additionally, this project will potentially identify new dysfunctional signaling pathways that are amenable to therapeutic targeting in AML.

Project 3: Lenalidomide as an Immune Modulating Agent for Chronic Lymphocytic Leukemia

Project Leaders: John Byrd, MD, Kristie Blum, MD, and Amy Johnson, PhD

Project 3 explores the mechanism of action of the unique agent lenalidomide in CLL, and seeks to develop new strategies to optimize its efficacy in this disease. The project leaders are pursuing further investigations of the drug lenalidomide, for which three different studies have demonstrated clinical activity but atypical toxicity of tumor flare in CLL patients. To date, the mechanism of action and toxicity of lenalidomide in CLL is not known. This project is derived from clinical and laboratory studies published by this group of Ohio State investigators showing that lenalidomide promotes CLL cell activation, and potentially life-threatening tumor flare. Concurrent with ongoing laboratory studies, a phase I clinical trial of lenalidomide in patients with symptomatic, previously treated disease and those with minimal residual disease immediately following treatment will be pursued.

Project 4: Preclinical and Clinical Investigation of MLL-PTD Acute Myeloid Leukemia

Project Leaders: Michael A. Caligiuri, MD and William Blum, MD

Project 4 directs translational and clinical efforts toward epigenetic therapy of a rare subset of AML with MLL-PTD. Drs. Caligiuri, Marcucci, and Blum will explore a discovery made in Dr. Caligiuri's laboratory that the well-characterized partial tandem duplication (PTD) of the MLL gene in a single allele occurs in a subset of patients with AML. Importantly, the lab also discovered that the wild type MLL allele in this same subset of patients may be silenced by epigenetic regulation, presenting an opportunity for drug-induced re-expression of the gene. The translational research group at Ohio State has been one of the leaders nationally in developing drugs that target epigenetic changes in leukemic cells and Project 4 will incorporate both preclinical and clinical aims. Notably, creation of a MLL PTD knock-in mouse demonstrated that the lesion described does not alone produce AML. Additional abnormalities such as FLT3 over-experssion resulted in development of leukemia in this mouse model. Thus, Project 4 will further characterize/validate and utilize this MLL PTD/FLT3 mouse as a preclinical model and also develop drug treatment strategies targeting epigenetic and genetic aberrations in patients with AML.

Project 5: Preclinical and Clinical Development of Silvestrol in Chronic Lymphocytic Leukemia

Project Leaders: Michael Grever, MD, and Robert Lee, PhD

Project 5 focuses on a new therapeutic target, the inhibition of protein translation, in CLL. This project utilizes the novel natural product silvestrol that was identified and characterized in part by Ohio State investigators. Drs. Grever and Lee have been working to translate silvestrol, derived from the Indonesian plant Aglaia foveolata, to clinical trials for patients with CLL. It has been demonstrated that silvestrol is selectively cytotoxic toward CLL cells through a mechanism that involves selective inhibition of translation of the anti-apoptotic protein Mcl-1. The Mcl-1 target has been validated by Ohio State Leukemia SPORE members and others as a critical anti-apoptotic Bcl-2 family member whose reduction directly results in apoptosis in CLL cells. Extending from these in vitro studies, the Leukemia SPORE project team also demonstrated in vivo activity of silvestrol in both the ES-TCL1 CLL model and an alternative lymphoid leukemia xenograft model. Preliminary pharmacokinetics studies suggest that silvestrol has a relatively short in vivo half-life. To improve the pharmacokinetic parameters of silvestrol, a nanoparticle-encapsulated formulation was developed by Dr. Lee that maintains in vitro activity and will greatly improve the in vivo pharmacology and efficacy. Preclinical studies to test in vivo the toxicity and the pharmacologic activity of silvestrol nanoparticles are ongoing.


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