ATPS-77THE KETONE BODY ß-HYDROXYBUTYRATE RADIOSENSITIZES GLIOBLASTOMA MULTIFORME STEM CELLS

Abstract

Glioblastoma multiforme (GBM) is a malignant brain tumor that typically recurs following standard treatment with surgery, radiation and chemotherapy. A rare population of radio-chemoresistant glioma stem cells (GSCs) is implicated in tumor repopulation and progression following treatment. Improvement in the prognosis of these patients requires the development of new therapeutic approaches. One emerging strategy is to target aberrant cell metabolism, a trait shared by virtually all tumor cells. The ketogenic diet (KD), a high fat, low carbohydrate and protein metabolic therapy has demonstrated anti-tumor effects alone, and in combination with radiation. The KD prolongs survival in animal glioma models, and when used in conjunction with radiation 9 of 11 mice were cured of their implanted tumors. We are now extending this work to determine if the ketone body, β-hydroxybutyrate (βHB) radiosensitizes human GSCs in vitro. The effects of βHB on growth were examined at various βHB concentrations in two GSC lines, L0 and L1. Both 5mM and 10mM βHB significantly reduced GSC growth. When coupled with 4Gy of radiation, 5mM βHB treatment significantly reduced L1 neurosphere formation and frequency, more than either βHB treatment or radiation alone. In L0, combination treatment significantly reduced neurosphere formation and frequency, more than radiation alone. To explore underlying mechanisms we are investigating the effect of βHB on DNA damage and repair in GSCs. Additionally, we are determining the effect of βHB on hypoxia within GSC neurospheres by analyzing expression of hypoxia inducible factor 1 alpha and the hypoxic marker carbonic anhydrase 9. We previously showed that the KD reduced the expression of these genes in a mouse glioma model. Taken altogether, these data suggest that βHB may sensitize GBMs to radiation by inhibiting growth of both glioma cells and GSCs, which may have implications for its use to treat tumor recurrence.