The broad, long-term goal of this proposal is to design better treatment for large granular lymphocyte (LGL) leukemia. LGL leukemia is a clonal lymphoproliferative disorder associated with bone marrow failure that results in anemia and/or neutropenia. The central hypothesis of this proposal is that an activated Ras-dependent anti-apoptotic pathway drives the survival of leukemic LGLs. We also hypothesize that dysregulated NK receptor expression contributes to lymphocyte-mediated bone marrow failure. We found that a Ras/ERK pathway is constitutively active in leukemic LGLs and that inhibition of this signaling pathway with farnyslytransferase inhibitors (FTIs) induces apoptosis (programmed cell death) in the leukemic cells. The overall goal of this proposal is to assess the therapeutic efficacy of targeted drug therapy with the farneslytransferase inhibitor tipifarnib (Zarnestra) for the treatment of LGL leukemia. The secondary goal is to understand the mechanism of treatment responses and treatment failures by pursuing correlative laboratory studies associated with a clinical trial. This trial will be conducted as a new initiative of the Bone Marrow Failures Consortium based at the Cleveland Clinic, Cleveland, OH. The feasibility of accomplishing the goals in this proposal will be enhanced by national patient recruitment through this Consortium.
Each specific aim will test a postulated mechanism of treatment efficacy that will also provide insights into the mechanism of pathogenesis of LGL leukemia:
Specific Aim 1 : to determine whether a Ras/ERK signaling pathway contributes to LGL cell survival;
Specific Aim 2 : to define the clonotypic population of leukemic T cells and NK cells and determine whether apoptosis sensitivity to Zarnestra correlates with a molecular response;
Specific Aim 3 : to determine whether dysregulated NK receptor expression contributes to disease pathogenesis. Correlative studies in Specific Aim 1 are designed to determine whether inhibition of the Ras transduction pathway mediates treatment responses to Zarnestra. We will measure whether treatment responses are correlated to farnysltransferase activity, FTase-regulated proteins, ERK activity, downstream anti-apoptotic proteins controlled by Ras and ERK, and other proteins known to be important for LGL cell survival. Correlative studies proposed in Specific Aim 2 should identify the clonal population using precise molecular techniques and include the development of a predictive in vitro apoptotic assay. Correlative studies proposed in Specific Aim 3 will measure the effect of NK receptors on bone marrow suppression. Results of these studies should identify important molecular targets for drug development in bone marrow failure syndromes.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA112112-02
Application #
7107961
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Howcroft, Thomas K
Project Start
2005-08-15
Project End
2009-05-31
Budget Start
2006-06-01
Budget End
2007-05-31
Support Year
2
Fiscal Year
2006
Total Cost
$293,055
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Yang, L; Mailloux, A; Rollison, D E et al. (2013) Naive T-cells in myelodysplastic syndrome display intrinsic human telomerase reverse transcriptase (hTERT) deficiency. Leukemia 27:897-906
Mailloux, Adam W; Zhang, Ling; Moscinski, Lynn et al. (2013) Fibrosis and subsequent cytopenias are associated with basic fibroblast growth factor-deficient pluripotent mesenchymal stromal cells in large granular lymphocyte leukemia. J Immunol 191:3578-93
Nyland, Susan Bell; Krissinger, Daniel J; Clemente, Michael J et al. (2012) Seroreactivity to LGL leukemia-specific epitopes in aplastic anemia, myelodysplastic syndrome and paroxysmal nocturnal hemoglobinuria: results of a bone marrow failure consortium study. Leuk Res 36:581-7
Powers, John J; Dubovsky, Jason A; Epling-Burnette, P K et al. (2011) A molecular and functional analysis of large granular lymphocyte expansions in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors. Leuk Lymphoma 52:668-79
Epling-Burnette, Pearlie K; Loughran Jr, Thomas P (2010) Suppression of farnesyltransferase activity in acute myeloid leukemia and myelodysplastic syndrome: current understanding and recommended use of tipifarnib. Expert Opin Investig Drugs 19:689-98
Yang, Jun; Liu, Xin; Nyland, Susan B et al. (2010) Platelet-derived growth factor mediates survival of leukemic large granular lymphocytes via an autocrine regulatory pathway. Blood 115:51-60
Epling-Burnette, Pearlie K; List, Alan F (2009) Advancements in the molecular pathogenesis of myelodysplastic syndrome. Curr Opin Hematol 16:70-6
Zou, J X; Rollison, D E; Boulware, D et al. (2009) Altered naive and memory CD4+ T-cell homeostasis and immunosenescence characterize younger patients with myelodysplastic syndrome. Leukemia 23:1288-96
Yang, Jun; Epling-Burnette, P K; Painter, Jeffrey S et al. (2008) Antigen activation and impaired Fas-induced death-inducing signaling complex formation in T-large-granular lymphocyte leukemia. Blood 111:1610-6
Epling-Burnette, Pearlie K; Bai, Fanqi; Painter, Jeffrey S et al. (2007) Reduced natural killer (NK) function associated with high-risk myelodysplastic syndrome (MDS) and reduced expression of activating NK receptors. Blood 109:4816-24

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