ET-36 * HYPERTHERMIA IMPROVES THE RADIOSENSITIVITY OF GLIOMA STEM CELLS BY INHIBITION OF AKT SIGNALING

Abstract

Glioblastoma (GBM) is the most prevalent and fatal type of primary brain tumor. Radiation is the most effective adjuvant therapy. Glioma stem cells (GSCs) are a subpopulation of cells that survive to self-renew and recapitulate the tumor. Hyperthermia is one of the most potent radiosensitizers and is re-emerging as a treatment option for patients with GBM. To determine mechanisms behind hyperthermic radiosensitization, we performed a screen by phospho-kinase array analysis. We identified suppression of AKT activation as a major mechanism for thermoradiosensitization of GSCs. Whereas GSCs exhibited increased AKT activity after irradiation, hyperthermia abrogated radiation-induced AKT activation to impair proliferation and promote apoptosis. Expression of a constitutively activated form of AKT in GSCs was able to restore radioresistance even with thermoradiotherapy. Pharmacologic inhibition of the AKT regulator PI3K further enhanced thermoradiosensitization. In a preclinical orthotopic xenotransplantation model of GBM, thermoradiotherapy suppressed the phosphorylation of the AKT downstream effector ribosomal protein S6, reduced tumor growth and extended animal survival. Together, these data support the use of combined hyperthermia and radiation for the treatment of glioblastoma.