Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy

• Published in: Oncotarget 2017-07, Vol.8 (29), p.47969-47983
• Main Authors: Agliano, Alice, Balarajah, Geetha, Ciobota, Daniela M, Sidhu, Jasmin, Clarke, Paul A, Jones, Chris, Workman, Paul, Leach, Martin O, Al-Saffar, Nada M S
• Format: Article
• Language: English
• Subjects: Adult; Animals; Biomarkers; Cell Line, Tumor; Cell Survival - drug effects; Cell Survival - radiation effects; Child; Choline - metabolism; Energy Metabolism - drug effects; Female; Glioblastoma - metabolism; Glioblastoma - radiotherapy; Glucose - metabolism; Humans; Imidazoles - pharmacology; Magnetic Resonance Spectroscopy - methods; Metabolomics - methods; Mice; Phosphoinositide-3 Kinase Inhibitors; Protein Kinase Inhibitors - pharmacology; Proton Magnetic Resonance Spectroscopy; Quinolines - pharmacology; Radiation Tolerance - drug effects; Radiation-Sensitizing Agents - pharmacology; Research Paper; Signal Transduction - drug effects; TOR Serine-Threonine Kinases - antagonists & inhibitors; X-Rays
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.18206

Poor outcome for patients with glioblastomas is often associated with radioresistance. PI3K/mTOR pathway deregulation has been correlated with radioresistance; therefore, PI3K/mTOR inhibition could render tumors radiosensitive. In this study, we show that NVP-BEZ235, a dual PI3K/mTOR inhibitor, potentiates the effects of irradiation in both adult and pediatric glioblastoma cell lines, resulting in early metabolic changes detected by nuclear magnetic resonance (NMR) spectroscopy. NVP-BEZ235 radiosensitises cells to X ray exposure, inducing cell death through the inhibition of CDC25A and the activation of p21cip1(CDKN1A). Lactate and phosphocholine levels, increased with radiation, are decreased after NVP-BEZ235 and combination treatment, suggesting that inhibiting the PI3K/mTOR pathway reverses radiation induced metabolic changes. Importantly, NVP-BEZ235 potentiates the effects of irradiation in a xenograft model of adult glioblastoma, where we observed a decrease in lactate and phosphocholine levels after seven days of combination treatment. Although tumor size was not affected due to the short length of the treatment, a significant increase in CASP3 mRNA was observed in the combination group. Taken together, our data suggest that NMR metabolites could be used as biomarkers to detect an early response to combination therapy with PI3K/mTOR inhibitors and radiotherapy in adult and pediatric glioblastoma patients.