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MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS

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 divided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes play an ess...

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Autores principales: Badodi, Sara, Marino, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260014/
http://dx.doi.org/10.1093/neuonc/noad073.249
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author Badodi, Sara
Marino, Silvia
author_facet Badodi, Sara
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 divided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes play an essential role in MB, particularly in the G4 subgroup. A BMI1(High);CHD7(Low) molecular signature identifies patients with poor survival. We have shown that BMI1(High);CHD7(Low) sustains MB growth through regulation of MAPK/ERK signalling and via epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display over-activation of MAPK/ERK and AKT/mTOR pathways leading to energetic rewiring characterised by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration and significantly extends survival in an in vivo pre-clinical model. Additionally, we identify a synergistic vulnerability of G4 MB to a combination treatment with BMI1 and MAPK/ERK inhibitors that overcomes the acquired resistance induced by single drug therapies. Importantly, we have now analysed recurrent G4 MB and found that the BMI1(High);CHD7(Low) signature is maintained at recurrence and it continues to predict the pharmacological vulnerabilities we previously described. Finally, we extended the analysis to other paediatric brain tumours, including histone mutant gliomas and ependymomas, and identified molecularly defined subgroups that exhibit differential response to the compounds predicted to be effective by the BMI1(High);CHD7(Low) signature, hence expanding the spectrum of tumour potentially amenable to these novel pharmacological approaches.
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spelling pubmed-102600142023-06-13 MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS Badodi, Sara Marino, Silvia Neuro Oncol Final Category: Medulloblastomas - MDB 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 divided into subtypes with different prognosis and responses to therapy. Deregulation of chromatin modifier genes play an essential role in MB, particularly in the G4 subgroup. A BMI1(High);CHD7(Low) molecular signature identifies patients with poor survival. We have shown that BMI1(High);CHD7(Low) sustains MB growth through regulation of MAPK/ERK signalling and via epigenetic regulation of inositol metabolism in both G4 MB cells and patients. These tumours display over-activation of MAPK/ERK and AKT/mTOR pathways leading to energetic rewiring characterised by enhanced glycolytic capacity and reduced mitochondrial function. We demonstrate that inositol administration counteracts this metabolic alteration and significantly extends survival in an in vivo pre-clinical model. Additionally, we identify a synergistic vulnerability of G4 MB to a combination treatment with BMI1 and MAPK/ERK inhibitors that overcomes the acquired resistance induced by single drug therapies. Importantly, we have now analysed recurrent G4 MB and found that the BMI1(High);CHD7(Low) signature is maintained at recurrence and it continues to predict the pharmacological vulnerabilities we previously described. Finally, we extended the analysis to other paediatric brain tumours, including histone mutant gliomas and ependymomas, and identified molecularly defined subgroups that exhibit differential response to the compounds predicted to be effective by the BMI1(High);CHD7(Low) signature, hence expanding the spectrum of tumour potentially amenable to these novel pharmacological approaches. Oxford University Press 2023-06-12 /pmc/articles/PMC10260014/ http://dx.doi.org/10.1093/neuonc/noad073.249 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (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 Final Category: Medulloblastomas - MDB
Badodi, Sara
Marino, Silvia
MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS
title MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS
title_full MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS
title_fullStr MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS
title_full_unstemmed MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS
title_short MDB-16. TARGETING EPIGENETIC DYSREGULATION IN PAEDIATRIC BRAIN TUMOURS
title_sort mdb-16. targeting epigenetic dysregulation in paediatric brain tumours
topic Final Category: Medulloblastomas - MDB
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260014/
http://dx.doi.org/10.1093/neuonc/noad073.249
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