Failure to eliminate minimal residual disease (MRD) continues to limit the success of chemotherapy in multiple myeloma (MM), acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). We propose the tumor microenvironment consists of specialized niches that contribute to de-novo resistance and ultimately to the failure to eliminate minimal (MRD) in hematopoietic tumors. One microenvironment that is particularly relevant to hematopoietic tumors is the bone marrow. The bone marrow microenvironment supports high local concentrations of cytokines, growth factors and components of extracellular matrixes. We previously showed that cell adhesion via beta 1 integrins to FN is sufficient to protect leukemic and MM cells from drug-induced apoptosis. We have referred to this phenotype as cell adhesion mediated drug resistance or CAM-DR. This proposal will investigate the role of Bim in mediating the CAM-DR phenotype. In addition, this proposal will delineate pathways and targets that are causative for reduced Bim levels in adhered cells. Finally, we will determine whether targeting beta 1 integrin mediated signaling increases the efficacy of chemotherapy in a bone marrow stroma and SCID-Hu model of drug resistance. To this end specific aim 1 of this grant will determine the overall contribution of reduced Bim levels in mediating the CAM-DR phenotype.
Specific aim 2 of this grant will determine whether post-translational regulation of Bim is causally related to reduced Bim levels in adherent cells.
In specific aim 3 of this proposal we will disrupt beta 1 integrin mediated signaling and determine whether this results in increased cell death induced by chemotherapy in a bone marrow stroma co-culture model and the SCID-Hu in vivo model. In summary, we hypothesize that cell adhesion mediated reduction in Bim levels is a critical determinant of CAM-DR and contributes to the failure of currently used cytotoxics to eliminate MRD in hematopoietic tumors. This hypothesis will be rigorously tested in this proposal. Relevance: The failure to eliminate minimal residual disease associated with hematopoietic tumors impedes the success of standard chemotherapy. In this proposal we will test whether disrupting beta 1 integrin mediated signaling increases the potency of standard chemotherapy in the bone marrow microenvironment.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122065-04
Application #
7837605
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Forry, Suzanne L
Project Start
2007-08-08
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$283,860
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
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Nair, Rajesh R; Gebhard, Anthony W; Emmons, Michael F et al. (2012) Emerging strategies for targeting cell adhesion in multiple myeloma. Adv Pharmacol 65:143-89
Nair, Rajesh R; Tolentino, Joel H; Argilagos, Raul F et al. (2012) Potentiation of Nilotinib-mediated cell death in the context of the bone marrow microenvironment requires a promiscuous JAK inhibitor in CML. Leuk Res 36:756-63
Emmons, Michael F; Gebhard, Anthony W; Nair, Rajesh R et al. (2011) Acquisition of resistance toward HYD1 correlates with a reduction in cleaved α4 integrin expression and a compromised CAM-DR phenotype. Mol Cancer Ther 10:2257-66
Nair, Rajesh R; Tolentino, Joel; Hazlehurst, Lori A (2010) The bone marrow microenvironment as a sanctuary for minimal residual disease in CML. Biochem Pharmacol 80:602-12
Nair, Rajesh R; Emmons, Michael F; Cress, Anne E et al. (2009) HYD1-induced increase in reactive oxygen species leads to autophagy and necrotic cell death in multiple myeloma cells. Mol Cancer Ther 8:2441-51
Bewry, Nadine N; Nair, Rajesh R; Emmons, Michael F et al. (2008) Stat3 contributes to resistance toward BCR-ABL inhibitors in a bone marrow microenvironment model of drug resistance. Mol Cancer Ther 7:3169-75