Abstract #0128

Metabolic modulation towards improved outcome in human glioblastoma model

Kavindra Nath¹, David Nelson¹, Jeffrey Roman¹, Sofya Osharovich¹, Saad Sheikh², Stepan Orlovskiy¹, Stephen Pickup¹, Dennis Leeper³, Yancey Gillespie⁴, Corrine Griguer⁵, Jay Dorsey², Mary Putt⁶, and Jerry Glickson¹

¹Radiology, University of Pennsylvania, Philadelphia, PA, United States, ²Radiation Oncology, University of Pennsylvania, Philadelphia, PA, United States, ³Radiation Oncology, Thomas Jefferson University, Philadelphia, PA, United States, ⁴Neurosurgery, University of Alabama, Birmingham, AL, United States, ⁵Radiation Oncology, University of Iowa, Iowa City, IA, United States, ⁶Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, United States

Standard of care for glioblastoma multiforme (GBM) patients, the Stupp protocol, involves radiotherapy concurrent with adjuvant temozolomide (TMZ) chemotherapy. Lonidamine (LND), an inhibitor of monocarboxylate transporters, mitochondrial pyruvate carrier and mitochondrial complex I & II, is shown to potentiate TMZ chemotherapy inhibiting the growth of U251 glioblastoma cells orthotopically implanted in mice. LND effects measured in vivo by ³¹P and ¹H MRS in subcutaneous U251 glioblastoma xenografts showed a sustained and tumor-selective decrease in intracellular pH, decrease in bioenergetics (βNTP/Pi) and an increase in lactate. Selective tumor acidification and deenergization induced by LND potentiated the TMZ response in U251 glioblastoma xenografts.

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