Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation

Sara Badodi, Nicola Pomella, Xinyu Zhang, Gabriel Rosser, John Whittingham, Maria Victoria Niklison-Chirou, Yau Mun Lim, Sebastian Brandner, Gillian Morrison, Steven M. Pollard, Christopher D. Bennett, Steven C. Clifford, Andrew Peet, M. Albert Basson and Silvia Marino ()
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Sara Badodi: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Nicola Pomella: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Xinyu Zhang: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Gabriel Rosser: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
John Whittingham: Centre for Craniofacial and Regenerative Biology, King’s College London
Maria Victoria Niklison-Chirou: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London
Yau Mun Lim: UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust
Sebastian Brandner: UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust
Gillian Morrison: The University of Edinburgh
Steven M. Pollard: The University of Edinburgh
Christopher D. Bennett: Institute of Cancer and Genomic Sciences, University of Birmingham
Steven C. Clifford: Newcastle University Centre for Cancer, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute
Andrew Peet: Institute of Cancer and Genomic Sciences, University of Birmingham
M. Albert Basson: Centre for Craniofacial and Regenerative Biology, King’s College London
Silvia Marino: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model.

Date: 2021
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DOI: 10.1038/s41467-021-22379-7

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