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Beta-blockers disrupt mitochondrial bioenergetics & increase radiotherapy efficacy independently of BAR in medulloblastoma

We are very proud to share our latest publication entitled : Beta-blockers disrupt mitochondrial bioenergetics and increase radiotherapy efficacy independently of beta-adrenergic receptors in medulloblastoma from Maïlys Rossia, Julie Talbot, Patricia Pirisa, Marion LeGrand, Marie-Pierre Montero, Mélanie Matteudi, Emilie Agavnian-Couquiaud, Romain Appay,Céline Keime Daniel Williamson, DujeBuricg, Véronique Bourgarel, Laetitia Padovani, Steven C.Clifford, Olivier Ayrault, Eddy Pasquier, Nicolas Andréa, Manon Carré. It is now available in eBioMedicine which is part of the Lancet Discovery Science.

This is a joint effort from :
- the Centre de Recherche en Cancérologie de Marseille (CRCM), Aix-Marseille Université, CNRS, Inserm, Institut Paoli Calmettes, Marseille, France
- the Institut Curie, Inserm, CNRS, Université Paris-Saclay, Orsay, France
- the Assistance Publique-Hôpitaux de Marseille (APHM), Marseille, France
- the Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS, Inserm, Université de Strasbourg, Illkirch-Graffenstaden, France
- the Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne, United Kingdom
- and the Metronomics Global Health Initiative, Marseille, France

The next step is to bring theses to the clinic through a phase 1 trial.

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.

the full text is available here freely through open access.