Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.628149
Title: Combination of Dasatinib and Dexamethasone targets the myeloma plasma cell through its interaction with the bone marrow microenvironment
Author: Arumugam Ramasamy, Karthikeyan
Awarding Body: King's College London (University of London)
Current Institution: King's College London (University of London)
Date of Award: 2012
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Abstract:
Dexamethasone therapy has been the backbone of myeloma treatment for the last few decades. Despite advances in chemotherapy, myeloma continues to be incurable and all patients eventually relapse with progressive disease. Cell adhesion mediated drug resistance and a permissive bone marrow microenvironment facilitates myeloma cell survival. Upto 90% of myeloma patients present with bone disease of varying degrees, which is a result of enhanced osteoclastic activity and reduced osteoblast differentiation and function. Dasatinib, a multi-targeted tyrosine kinase inhibitor, inhibits the Src family kinases, Abl kinase, c- kit and PDGFR. I hypothesised, combining Dasatinib with a cytotoxic agent dexamethasone; through direct antimyeloma effect, disruption of osteoclast cytoskeleton and adhesion of plasma cells to the bone marrow microenvironment, would enhance tumour sensitivity to steroids. In plasma cells, combination of Dasatinib and dexamethasone at clinically relevant concentrations induced apoptosis of human myeloma cell lines and exhibited synergy. Cell cycle analysis showed reduction in the proliferative compartment (G2/M) and increase in the non-viable (SubG0) population indicating cell death by apoptosis also confirmed by Annexin V staining. Dasatinib and Dexamethasone combination inhibited secretion of IL-6 in cocultures of fibroblastic stromal cells and plasma cells but not MIP – 1 α in myeloma cells. Dasatinib inhibited adhesion of plasma cells on Fibronectin (FN) despite integrin activation. This effect correlated with down regulation of Src and Abl activity. Both Dasatinib and Dexamethasone inhibited adhesion of PC on stromal cells and osteoclasts. Dasatinib disrupted the organisation of actin cytoskeleton in osteoclasts and blocked osteoclast maturation. Similar effect was observed with PP2 a Src inhibitor, confirming that the effects were mediated at least in part through Src inhibition. This effect resulted in impaired osteoclast function, evidenced by reduced in vitro bone resorption. A novel in vitro coculture system comprising eGFP expressing MM cell lines was designed and validated with available methods to screen drugs when plasma cells were cocultured with accessory cells in the microenvironment. Using this system, I found the combination of dasatinib with dexamethasone overcomes the protective effect of fibroblastic stromal cells and osteoclasts and induces apoptosis of myeloma cells. I conclude that Dasatinib would overcome resistance of myeloma cells to dexamethasone in the presence of stromal cells and osteoclasts. These findings warrant exploring this drug combination in steroid resistant myeloma patients with extensive skeletal disease in a phase I/II trial.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.628149  DOI: Not available
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