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EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION
Medulloblastoma (MB) is the most common paediatric malignant brain tumour and is classified into four distinct molecular subgroups (WNT, SHH, G3 and G4), each of them further subdivided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes plays an...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168266/ http://dx.doi.org/10.1093/neuonc/noab090.028 |
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author | Badodi, Sara Pomella, Nicola Zhang, Xinyu Morrison, Gillian Pollard, Steve M Bennett, Christopher D Clifford, Steven C Peet, Andrew Marino, Silvia |
author_facet | Badodi, Sara Pomella, Nicola Zhang, Xinyu Morrison, Gillian Pollard, Steve M Bennett, Christopher D Clifford, Steven C Peet, Andrew Marino, Silvia |
author_sort | Badodi, Sara |
collection | PubMed |
description | Medulloblastoma (MB) is the most common paediatric malignant brain tumour and is classified into four distinct molecular subgroups (WNT, SHH, G3 and G4), each of them further subdivided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes plays an essential role in MB, particularly in the G4 subgroup, the least understood of all subgroups, despite being the most common and associated with poor prognosis. A BMI1(High); CHD7(Low) molecular signature identifies patients with poor survival within this subgroup. We show that BMI1(High); CHD7(Low) mediates a novel epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display hyperactivation of the AKT/mTOR pathway which leads to energetic rewiring characterized by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration, impairs MB proliferation in vitro and significantly extends survival in an in vivo pre-clinical model. Moreover, inositol synergises with cisplatin, a chemotherapy agent currently used in MB treatment, enhancing its therapeutic effect in vivo. Importantly, cerebellar neural stem cells bearing the BMI1(High); CHD7(Low) signature do not show metabolic adaptation and are thus resistant to inositol treatment, highlighting a fundamental difference between normal and neoplastic metabolism in the developing cerebellum. In summary, we have identified an actionable vulnerability in a pre-clinical setting modelling a molecularly defined group of MB patients, the translational value of which can now be explored in signature-matched clinical trials in MB. |
format | Online Article Text |
id | pubmed-8168266 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-81682662021-06-02 EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION Badodi, Sara Pomella, Nicola Zhang, Xinyu Morrison, Gillian Pollard, Steve M Bennett, Christopher D Clifford, Steven C Peet, Andrew Marino, Silvia Neuro Oncol Embryonal Tumors Medulloblastoma (MB) is the most common paediatric malignant brain tumour and is classified into four distinct molecular subgroups (WNT, SHH, G3 and G4), each of them further subdivided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes plays an essential role in MB, particularly in the G4 subgroup, the least understood of all subgroups, despite being the most common and associated with poor prognosis. A BMI1(High); CHD7(Low) molecular signature identifies patients with poor survival within this subgroup. We show that BMI1(High); CHD7(Low) mediates a novel epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display hyperactivation of the AKT/mTOR pathway which leads to energetic rewiring characterized by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration, impairs MB proliferation in vitro and significantly extends survival in an in vivo pre-clinical model. Moreover, inositol synergises with cisplatin, a chemotherapy agent currently used in MB treatment, enhancing its therapeutic effect in vivo. Importantly, cerebellar neural stem cells bearing the BMI1(High); CHD7(Low) signature do not show metabolic adaptation and are thus resistant to inositol treatment, highlighting a fundamental difference between normal and neoplastic metabolism in the developing cerebellum. In summary, we have identified an actionable vulnerability in a pre-clinical setting modelling a molecularly defined group of MB patients, the translational value of which can now be explored in signature-matched clinical trials in MB. Oxford University Press 2021-06-01 /pmc/articles/PMC8168266/ http://dx.doi.org/10.1093/neuonc/noab090.028 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) ), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Embryonal Tumors Badodi, Sara Pomella, Nicola Zhang, Xinyu Morrison, Gillian Pollard, Steve M Bennett, Christopher D Clifford, Steven C Peet, Andrew Marino, Silvia EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION |
title | EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION |
title_full | EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION |
title_fullStr | EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION |
title_full_unstemmed | EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION |
title_short | EMBR-10. INOSITOL TREATMENT INHIBITS MEDULLOBLASTOMA THROUGH SUPPRESSION OF EPIGENETIC-DRIVEN METABOLIC ADAPTATION |
title_sort | embr-10. inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation |
topic | Embryonal Tumors |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168266/ http://dx.doi.org/10.1093/neuonc/noab090.028 |
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