MODL-01.  In-vivo evaluation of the cytotoxic and radiosensitizing effect of arsenic trioxide (ATO) in SHH-activated/TP53-mutant medulloblastoma subgroup.

Abstract Patients with medulloblastoma (MB) of the SHH-activated/TP53-mutant subgroup have a particularly unfavorable prognosis, despite standard treatment. To assess whether arsenic trioxide (ATO; a SHH-pathway inhibitor) has cytotoxic and radiosensitizing effects with an impact on survival in animal models of MB we studied the efficacy of ATO alone or combined with radiotherapy (RT) in TP53-mutant MB xenografts. Orthotopic tumor models were generated using a DAOY cell line, transfected with luciferase. After tumor establishment, the animals (n = 34) were divided into four treatment groups: group 01 (control; n = 9), group 02 (ATO; n = 8), group 03 (radiotherapy; n = 8), and group 04 (ATO associated with radiotherapy; n = 9). ATO was administered at a dose of 5 mg/kg/day, intraperitoneally, for 10 consecutive days, and radiotherapy was administered in 3 fractions (180cGy/fraction) on alternate days. The animals were monitored clinically and through weekly bioluminescence imaging. Survival rates, tumor progression by bioluminescence intensity, and anatomopathological findings were evaluated. There was no significant difference in the survival of the animals in the different treatment groups. Immediately after treatment, the group that received ATO+RT had a significant reduction in tumor bioluminescence. Yet, this antitumoral effect was not maintained in subsequent evaluations. There were no significant differences in the anatomopathological findings (tumor size, necrosis, and mitotic indexes) between groups. ATO, alone or combined with RT, did not produce signs of recognizable systemic toxicity. The combination of ATO with RT was not capable of increasing survival in animals with TP53-mutated MB SHH in this preclinical model. Molecular studies using the RNAseq technique are being performed and may reveal new relevant findings regarding the molecular mechanism of ATO action on the SHH pathway. These results reinforce that, although many advances have been made in the molecular basis of MB subtypes, translating them into new effective therapies remains challenging. Support: CNPq and FAEPA.