GLUT1 inhibitor as targeted therapy for SDH deficient tumors

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 the formation of hereditary Paraganglioma, Phaeochromocytoma, Gastrointestinal Stromal Tumors, Renal Oncocytoma and Renal Cell Carcinoma. Effective therapies for SDH-deficient cancer have not been established yet and are urgently needed.

Metabolomics studies using 13C-labeled glucose revealed a dramatic increase in glucose metabolism. 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. We therefore hypothesized that inhibiting glycolysis by blocking glucose uptake can be lethal to SDH deficient cancer cells.

To this end, we used a commercially available inhibitor of glucose transporter GLUT1, BAY-876 (Sigma-Aldrich, Israel). First, we demonstrated the efficacy of the inhibitor in vitro on SDH deficient mouse kidney cell line. The compound decreased viability of SDH deficient cells while sparing wild type cells. Next, we established an in vivo model of subcutaneous SDH deficient cell line derived xenografts. Mice were treated with BAY-876 O.P. daily following cell injection and Tumor volume was measured throughout the experiment. BAY-876 inhibited the growth of SDH deficient tumors in vivo, and prolonged the survival of treated mice.

Our results provide evidence that GLUT1 inhibitor can be used as a targeted therapy for SDH deficient malignancies.