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Sofia Ferreira

Séminaire Jeunes Docteurs du GDR MI2B  du 1er février 2021

Title: Inhibiting DNA repair with AsiDNA to radiosensitize pediatric brain tumors without added toxicity

Authors: Sofia Ferreira, Chloe Foray, Alberto Gatto, Magalie Larcher, Sophie Heinrich, Mihaela Lupu, Joel Mispelter, François D. Boussin, Célio Pouponnot and Marie Dutreix

Abstract: Medulloblastoma is a brain tumor of the cerebellum. It is an important cause of mortality and morbidity in pediatric oncology. Preclinical and clinical evidence showed that the DNA repair inhibitor AsiDNA improves treatments efficacy without added toxicity in adults. In our work, we investigated whether these properties of AsiDNA could be translated to medulloblastoma pediatric models, addressing a significant unmet clinical need in medulloblastoma care.
To evaluate the brain permeability of AsiDNA upon systemic delivery, we intraperitoneally injected a fluorescence form of AsiDNA in models harboring brain tumors and in models still in development. Studies evaluated toxicity associated with combination of AsiDNA with radiation in the treatment of young developing animals at subacute levels, related to growth and development, and at chronic levels, related to brain organization and cognitive skills. Efficacy of the combination of AsiDNA with radiation was tested in two different preclinical xenografted models of high-risk medulloblastoma and in a panel of medulloblastoma cell lines from different molecular subgroups and TP53 status. Role of TP53 on the AsiDNA-mediated radiosensitization was analyzed by RNA-sequencing, DNA repair recruitment, and cell death assays.
Capable of penetrating young brain tissues, AsiDNA showed no added toxicity to radiation. Combination of AsiDNA with radiotherapy improved the survival of animal models more efficiently than increasing radiation doses. Medulloblastoma radiosensitization by AsiDNA was not restricted to a specific molecular group or status of TP53. Molecular mechanisms of AsiDNA, previously observed in adult malignancies, were conserved in pediatric models and resembled dose increase when combined with irradiation.
Our results suggest that AsiDNA is an attractive candidate to improve radiotherapy in medulloblastoma, with no indication of additional toxicity in developing brain tissues.


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