Establishing a Clinically Relevant Radiation Therapy Method for Preclinical Medulloblastoma Research.
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PURPOSE: Craniospinal irradiation (CSI) is a cornerstone of pediatric brain cancer therapy, yet detailed, reproducible protocols for accurate CSI delivery in preclinical mouse models remain scarce, hindering translational research and the development of radiosensitizing strategies. We aimed to establish a clinically relevant, easily replicable radiation therapy protocol for medulloblastoma (MB) mouse models, providing a robust platform for preclinical evaluation of novel therapeutic combinations. We hypothesized that multifraction CSI would most closely mirror clinical practice and achieve clinically representative disease control. METHODS AND MATERIALS: Four radiation therapy strategies were compared to optimize treatment of orthotopic MB xenografts in mice: highly focal irradiation, regional brain targeting, whole brain exposure, and CSI. Mice received fractionated X-ray treatment using an X-RAD SmART 225Cx system. Survival was assessed by Kaplan-Meier analysis, recurrence patterns by histology, and DNA damage response activation by immunohistochemistry. RESULTS: We evaluated 7 commonly used MB models (D283, D425, SU-MB002, MED813FH, MED211FH, TK-MB913, and a murine allograft). Focal irradiation provided minimal disease control, whereas regional brain targeting extended survival but failed to prevent rapid regrowth. Whole brain irradiation delayed progression but allowed spinal metastases. In contrast, multifraction CSI significantly improved survival across all models, with recurrence localized to the implantation site. Immunohistochemistry confirmed activation of DNA damage response pathways and cell cycle arrest, with distinct patterns between TP53-wildtype and TP53-mutated models. CONCLUSIONS: Multifraction CSI most accurately replicates clinical treatment and relapse patterns, outperforming focal and whole brain approaches. By defining CSI as the optimal strategy, we provide a clinically aligned, reproducible protocol with optimized dosing for common MB models, that will accelerate translational research and drive the development of next-generation radiosensitizers for pediatric brain tumors.