Service d'anatomie pathologique et de neuropathologie, Hôpital de la Timone, Assistance Publique-Hôpitaux de Marseille (APHM), Marseille, France
Céline Keime
Plateforme GenomEast, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, Inserm, Université de Strasbourg, Illkirch-Graffenstaden, France
Daniel Williamson
Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom
Duje Buric
Institut Méditerranéen de Biodiversité et d’Écologie marine et continentale (IMBE), Aix-Marseille Université, CNRS, IRD, Avignon Université, Marseille, France
Véronique Bourgarel
Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, CNRS, Inserm, Institut Paoli Calmettes, Marseille, France
Laetitia Padovani
Service de Radiothérapie, Timone Hospital, Assistance Publique-Hopitaux de Marseille (AP-HM), Marseille, France
Steven C. Clifford
Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom
Olivier Ayrault
Institut Curie, Inserm, CNRS, Université Paris-Saclay, Orsay, France
Eddy Pasquier
Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, CNRS, Inserm, Institut Paoli Calmettes, Marseille, France; Metronomics Global Health Initiative, Marseille, France
Nicolas André
Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, CNRS, Inserm, Institut Paoli Calmettes, Marseille, France; Metronomics Global Health Initiative, Marseille, France; Service d'Hématologie & Oncologie Pédiatrique, Timone Hospital, AP-HM, Marseille, France; Corresponding authors at: Centre de Recherche en Cancérologie de Marseille (CRCM), Faculté de Pharmacie, 27 Boulevard Jean Moulin 13005 Marseille, France.
Manon Carré
Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, CNRS, Inserm, Institut Paoli Calmettes, Marseille, France; Corresponding authors at: Centre de Recherche en Cancérologie de Marseille (CRCM), Faculté de Pharmacie, 27 Boulevard Jean Moulin 13005 Marseille, France.
Summary: Background: Medulloblastoma is the most frequent brain malignancy of childhood. The current multimodal treatment comes at the expense of serious and often long-lasting side effects. Drug repurposing is a strategy to fast-track anti-cancer therapy with low toxicity. Here, we showed the ability of β-blockers to potentiate radiotherapy in medulloblastoma with bad prognosis. Methods: Medulloblastoma cell lines, patient-derived xenograft cells, 3D spheroids and an innovative cerebellar organotypic model were used to identify synergistic interactions between β-blockers and ionising radiations. Gene expression profiles of β-adrenergic receptors were analysed in medulloblastoma samples from 240 patients. Signaling pathways were explored by RT-qPCR, RNA interference, western blotting and RNA sequencing. Medulloblastoma cell bioenergetics were evaluated by measuring the oxygen consumption rate, the extracellular acidification rate and superoxide production. Findings: Low concentrations of β-blockers significantly potentiated clinically relevant radiation protocols. Although patient biopsies showed detectable expression of β-adrenergic receptors, the ability of the repurposed drugs to potentiate ionising radiations did not result from the inhibition of the canonical signaling pathway. We highlighted that the efficacy of the combinatorial treatment relied on a metabolic catastrophe that deprives medulloblastoma cells of their adaptive bioenergetics capacities. This led to an overproduction of superoxide radicals and ultimately to an increase in ionising radiations-mediated DNA damages. Interpretation: These data provide the evidence of the efficacy of β-blockers as potentiators of radiotherapy in medulloblastoma, which may help improve the treatment and quality of life of children with high-risk brain tumours. Funding: This study was funded by institutional grants and charities.
