Determinants of Pharmacodynamic Heterogeneity in Multiple Myeloma Cells
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Multiple myeloma is a complex heterogeneous hematological malignancy comprising of rapidly proliferating genetically diverse clonal plasma cells. Tumor initiation, development, and progression occur through a series of pre-malignant stages, with sequential acquisition of genomic aberrations. The developing genomic landscape offers opportunity for microenvironment, drug treatment, and immune system related selection pressures to introduce various somatic mutations providing a fitness advantage to cell populations and leading to a branching evolutionary scheme of clonal evolution. Clonal evolution—a process that mimics Darwinian evolution—enables coexistence of heterogeneous clonal and sub-clonal populations providing myeloma cells the ability to acclimatize and grow as the disease progresses. The inter-clonal heterogeneity is the primary cause for variable responses to drug treatment between patients and within the same patient at different times. The prevalence of specific sub-clones over others results in recurring cycles of remission and relapse in patients, eventually leading to refractory relapse. This therapeutic challenge necessitates the need to study the determinants of heterogeneous responses in myeloma patients to monitor disease progression, via prognostic biomarkers, and devise strategies for the implementation of personalized precision medicine. The purpose of the work presented in this dissertation is to investigate the determinants of heterogeneity in drug treatment response of molecularly different in vitro myeloma cell lines representing clonal populations of cells. This research employs a quantitative systems pharmacology approach to explore the heterogeneous intracellular signaling mechanisms governing drug action in myeloma cells and to identify common protein biomarkers associated with differing drug sensitivities as useful tools for translatable patient risk stratification and response prediction.