dc.contributor.author | Agliano, A | |
dc.contributor.author | Balarajah, G | |
dc.contributor.author | Ciobota, DM | |
dc.contributor.author | Sidhu, J | |
dc.contributor.author | Clarke, PA | |
dc.contributor.author | Jones, C | |
dc.contributor.author | Workman, P | |
dc.contributor.author | Leach, MO | |
dc.contributor.author | Al-Saffar, NMS | |
dc.date.accessioned | 2017-07-05T10:35:40Z | |
dc.date.issued | 2017-07-18 | |
dc.identifier.citation | Oncotarget, 2017, 8 (29), pp. 47969 - 47983 | |
dc.identifier.issn | 1949-2553 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/679 | |
dc.identifier.eissn | 1949-2553 | |
dc.identifier.doi | 10.18632/oncotarget.18206 | |
dc.description.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. | |
dc.format | Print | |
dc.format.extent | 47969 - 47983 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | IMPACT JOURNALS LLC | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.subject | Cell Line, Tumor | |
dc.subject | Animals | |
dc.subject | Humans | |
dc.subject | Mice | |
dc.subject | Glioblastoma | |
dc.subject | Choline | |
dc.subject | Imidazoles | |
dc.subject | Quinolines | |
dc.subject | Glucose | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Radiation-Sensitizing Agents | |
dc.subject | Magnetic Resonance Spectroscopy | |
dc.subject | Signal Transduction | |
dc.subject | Cell Survival | |
dc.subject | Energy Metabolism | |
dc.subject | X-Rays | |
dc.subject | Radiation Tolerance | |
dc.subject | Adult | |
dc.subject | Child | |
dc.subject | Female | |
dc.subject | Metabolomics | |
dc.subject | TOR Serine-Threonine Kinases | |
dc.subject | Proton Magnetic Resonance Spectroscopy | |
dc.subject | Biomarkers | |
dc.subject | Phosphoinositide-3 Kinase Inhibitors | |
dc.title | Pediatric and adult glioblastoma radiosensitization induced by PI3K/mTOR inhibition causes early metabolic alterations detected by nuclear magnetic resonance spectroscopy. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2017-04-29 | |
rioxxterms.versionofrecord | 10.18632/oncotarget.18206 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2017-07 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Oncotarget | |
pubs.issue | 29 | |
pubs.notes | Not known | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Magnetic Resonance | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.organisational-group | /ICR | |
pubs.organisational-group | /ICR/Primary Group | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Signal Transduction & Molecular Pharmacology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Molecular Pathology/Glioma Team | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging | |
pubs.organisational-group | /ICR/Primary Group/ICR Divisions/Radiotherapy and Imaging/Magnetic Resonance | |
pubs.organisational-group | /ICR/Primary Group/Royal Marsden Clinical Units | |
pubs.publication-status | Published | |
pubs.volume | 8 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Signal Transduction & Molecular Pharmacology | |
icr.researchteam | Glioma Team | |
icr.researchteam | Magnetic Resonance | |
dc.contributor.icrauthor | Clarke, Paul | |
dc.contributor.icrauthor | Jones, Chris | |
dc.contributor.icrauthor | Workman, Paul | |
dc.contributor.icrauthor | Leach, Martin | |
dc.contributor.icrauthor | Al-Saffar, Nada | |