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 Bennett, Steven C. Clifford, Andrew C. Peet, M. Albert Basson, Silvia Marino
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 BMI1 High ;CHD7 Low 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 BMI1 High ;CHD7 Low xenograft model.