AsiDNA is a radiosensitizer with no added toxicity in medulloblastoma pediatric models

AsiDNA is a radiosensitizer with no added toxicity in medulloblastoma pediatric models:

Purpose: Medulloblastoma (MB) is an important cause of mortality and morbidity in pediatric oncology. Here we investigated whether the DNA repair inhibitor AsiDNA could help address a significant unmet clinical need in MB care, by improving radiotherapy efficacy without increasing radiation-associated toxicity. Experimental Design: To evaluate the brain permeability to AsiDNA upon systemic delivery, we injected intraperitoneally a fluorescent form of AsiDNA in models harboring brain tumors and in development. Studies evaluated toxicity associated to combination of AsiDNA with radiation in the treatment of young developing animals at subacute, related to growth and development, and 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 MB, and in a panel of MB cell lines from different molecular subgroups and TP53 status. Role of TP53 on the AsiDNA-mediated radiosensitization was analyzed by RNA-Seq, DNA repair recruitment and cell death assays. Results: 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. MB radiosensitization by AsiDNA was not restricted to a specific molecular group or status of TP53. Molecular mechanisms of AsiDNA, previously observed in adult malignancies, are conserved in pediatric models and resemble dose increase when combined with irradiation. Conclusions: Our results suggest that AsiDNA is an attractive candidate to improve radiation therapy in MB, with no indication of additional toxicity in developing brain tissues.