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

Alice Agliano,Geetha Balarajah,Paul Workman,Paul A Clarke,Nada M.S Al-Saffar,Chris Jones,Jasmin Sidhu,Martin O Leach,Daniela M Ciobota

doi:10.18632/oncotarget.18206

Alice Agliano, Geetha Balarajah + Show 7 more

Open Access

https://doi.org/10.18632/oncotarget.18206

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Abstract

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.

Highlights

Glioblastoma (GBM, WHO grade IV) is the most common primary malignant brain tumor [1]
We show that NVP-BEZ235, a dual phosphatidyl www.impactjournals.com/oncotarget inositol 3-kinase (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
Resistance to radiation has been linked to activation of the PI3K pathway, as activated AKT accelerates repair of the DNA double-strand breaks induced by radiation and, improves post-irradiation cell survival [34, 35]

Summary

Introduction

Glioblastoma (GBM, WHO grade IV) is the most common primary malignant brain tumor [1]. Pediatric tumors (pGBM) are identical to those arising in adults (aGBM), the infratentorial region is often affected in children and the supratentorial area is the most common site in adults [1]. The current standard of care for newly diagnosed GBM is surgery followed by radiotherapy [6]. Radiotherapy was the first adjuvant therapy to demonstrate a significant survival benefit in aGBM [7] and was subsequently adopted as a standard therapy for pGBM. The administration of temozolomide alongside radiation [6] is currently the standard regimen for newly diagnosed aGBM. This strategy is less effective for pGBM patients, with temozolomide adding only a modest survival benefit [8]

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