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imf research grants archive

Bone marrow microenvironment and multiple myeloma chemotherapy optimization
Ariosto Silva, PhD
H. Lee Moffitt Cancer and Research Institute
Tampa, FL, USA
While systemic chemotherapy for myeloma is often initially quite successful, tumor sites that are resistant to therapy invariably remain as minimum residual disease (MRD) even after high-dose treatment. The mechanisms of resistance to chemotherapy include both micro-environmental and cellular factors such as (1) regional hypoxia in bone marrow resulting in decreased drug effectiveness due to absence of intermediate oxygen free radicals, (2) environmentally mediated resistance (EMDR) due to signaling between tumor cells and extracellular matrix (ECM), bone marrow stromal cells (BMS), and endothelial cells (EC), and (3) phenotypic resistance through upregulation of xenobiotic metabolism or DNA repair pathways. Dr. Silva and colleagues will examine these complex systems using an approach characterized as "integrated mathematical oncology" in which mathematical models are combined in an iterative way with in vivo and in vitro experiments. Ultimately, through understanding of the dynamics that govern emergence of chemotherapy resistance in myeloma, this research project will explore alternative treatment strategies based on understanding these dynamics to slow the evolution and growth of resistant phenotypes.
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