Emory University School of Medicine
Our research centers on investigating mechanisms underlying abnormal glucose utilization and the impact of enhanced glucose utilization on cell survival and proliferation in the hematological malignancy multiple myeloma. We currently have some exciting observations on the contributions of GLUT1-independent glucose uptake in myeloma, with extensions into other hematological malignancies and solid tumors. In 2009 we determined that myeloma cells rely on the insulin-responsive glucose transporter GLUT4 for glucose transport. We also demonstrated that myeloma cells exhibit elevated constitutive plasma membrane localized GLUT4 that is in part due to increased activity of the RabGTPase activating protein AS160_v2. Suppression of GLUT4 expression in myeloma cells leads to leads to significant reduction of the pro-survival BCL-2 family member, MCL-1 (myeloid cell leukemic factor 1). Given in the importance of MCL-1 in promoting resistance to a number of chemotherapeutics we are interested in furthering our understanding of how GLUT4 activity and glucose maintain MCL-1 expression. We are elucidating the upstream metabolite-driven signaling pathways that ultimately translate to regulating MCL-1 transcription. Myeloma cells resistant to GLUT4 suppression appear to engage alternate mitochondrial substrates to maintain viability. We are identifying critical compensatory metabolites though metabolite drop-out studies with evaluation of mitochondrial function and viability. Our long term objective is to identify and validate bio-markers that can aid in stratification of patients suitable for GLUT4-directed therapy.
From a translational perspective, we were fortunate to identify a HIV protease inhibitor that has an off-target inhibitory effect on GLUT4 activity. Ritonavir recapitulates the phenotypes elicited upon GLUT4 suppression or glucose-free culture of MM cells. We recently demonstrated the efficacy of ritonavir in an in vivo mouse xenograft model of myeloma. In addition, we demonstrated that any compensatory metabolism could be suppressed by the co-administration of the anti-diabetic drug metformin. HIV patients chronically treated with ritonavir who exhibit diabetic symptoms have been treated with metformin indicating this treatment combination is well tolerated in humans. We are now in the process of re-purposing these drugs for a phase I/II trial in refractory myeloma and CLL. Our studies have now provided the impetus for the identification of more potent selective GLUT4 targeting agents. Through in silico modeling of GLUT4 and pharmacophore screening of a small molecule compound library we have identified some promising hits. These compounds selectively target GLUT4, not GLUT1 and we are in the process of validating biological activity.
Our long-term goal is to improve our understanding of the molecular and cellular basis of enhanced glucose utilization in myeloma and other glycolytic cancers. These studies will enable us to investigate the intersection between glucose metabolism and resistance mechanisms and elucidate the basis of the metabolic plasticity of cancer that fosters the development of aggressive resistant cancer.
Investigating mechanisms underlying abnormal glucose utilization and the impact of enhanced glucose utilization on cell survival and proliferation in the hematologic malignancies multiple myeloma (MM) and CLL. The long-term objectives of my research are to 1) Improve our understanding of the molecular and cellular basis of enhanced glucose utilization in myeloma and other glycolytic cancers 2) Elucidate molecular mechanisms contributing to apoptosis sensitivity following GLUT4 inhibition in multiple myeloma and 3) Demonstrate the feasibility and therapeutic promise of targeting GLUT4 in myeloma by employing in vivo disease models and generation of selective GLUT4 inhibitors 4) Explore biological functions of novel glucose transporters 8 and 11 in myeloma pathobiology.
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