|M.Sc Student||Sneh Tal|
|Subject||Pharmaceutical Approaches for Targeting SDH Deficient|
|Department||Department of Medicine||Supervisor||Professor Eyal Gottlieb|
|Full Thesis text|
Succinate Dehydrogenase (SDH) is a hetero-tetrameric mitochondrial enzyme complex responsible for the oxidation of succinate to fumarate in the tricarboxylic acid cycle (TCA), a crucial step in oxidative phosphorylation. Loss-of-function mutations in any of the genes encoding SDH subunits are associated with increased cancer risk and are linked to hereditary Paraganglioma, Phaeochromocytoma, Gastrointestinal Stromal Tumors, Renal Oncocytoma and Renal Cell Carcinoma. Effective therapies for SDH deficient cancers have not been established yet and are urgently needed.
Lacking a key TCA cycle enzyme, SDH deficient cancer cells rely heavily on glycolysis for energy production and macromolecular synthesis to maintain rapid cell proliferation. Indeed, metabolomics studies in SDH deficient cells revealed a dramatic increase in glucose metabolism. We therefore hypothesized that inhibiting glycolysis by blocking glucose uptake would be specifically detrimental to SDH deficient cancer cells.
To this end, we used MTB-8265, a newly discovered glucose uptake inhibitor that was found to be synthetic lethal to SDH deficient cells. We also used BAY-876, a commercially available inhibitor of glucose transporter 1 (GLUT1). First, we demonstrated the efficacy of the inhibitors to inhibit glucose uptake in-vivo by monitoring blood glucose levels. Next, we established an in-vivo model of subcutaneous SDH deficient cell line derived xenografts. Mice were treated with both inhibitors daily following cell injection and tumor volume was measured throughout the experiments. MTB-8265 found to be toxic in low doses and did not inhibit growth of SDH deficient tumors while BAY-876 significantly inhibited the growth of SDH deficient tumors, and prolonged the survival of treated mice. Our results provide evidence that GLUT1 inhibitor can be used as a specific therapy for SDH deficient malignancies by targeting their unique metabolic vulnerabilities.