EMBR-10_Sara Badodi


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Sara Badodi1, Nicola Pomella1, Xinyu Zhang1, Gillian Morrison2, Steve M. Pollard2, Christopher D. Bennett3,4, Steven C. Clifford5, Andrew Peet3,4, Silvia Marino1;

1Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom. 2Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, United Kingdom. 3Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom. 4Birmingham Children’s Hospital, Birmingham, United Kingdom. 5Newcastle University Centre for Cancer, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom

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 BMI1High; CHD7Low molecular signature identifies patients with poor survival within this subgroup. We show that BMI1High; CHD7Low 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 BMI1High; CHD7Low 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.

Duration: 04:04

Posted: Sunday, June 6, 2021

Video tags: 2021 SNO Pediatric Meeting