Medulloblastoma is the most common malignant brain tumour of childhood. Four molecularly distinct subgroups exist, and each respond differently to current therapy. Animal models that accurately recapitulate the genotypes and phenotypes of each subgroup are rare but essential to evaluate potential new therapies and introduce novel subgroup-specific treatment protocols to the clinic. The XRAD image-guided, small animal radiotherapy (SmART) system is a unique instrument that combines micro-CT imaging and precision irradiation to deliver focal radiotherapy to specific targets, including the murine cerebral cortex or cerebellum. Our aim was to optimise preclinical radiotherapy protocols in mouse models of medulloblastoma that represent the three subgroups with the poorest prognosis.
At the onset of tumour-related symptoms, acute radiotherapy was administered to tumours in 2Gy fractions to mimic clinical dosages. Focal targeting was achieved using a rotating 5mm diameter X-ray beam. To minimise irradiation of surrounding normal tissues, arcs of either 60°, 70° or 80° were evaluated. Tumour tissue was harvested at 0.5, 2, 6 or 24 hours post-treatment, and immunohistochemical markers of DNA damage and apoptosis were used to evaluate therapeutic efficacy.
A transgenic model of SHH-subtype medulloblastoma (NeuroD2::SmoA1) demonstrated exquisite sensitivity to irradiation with significantly increased DNA damage and apoptosis two hours post-treatment (p = 0.0002 and 0.0025 respectively). Moreover, reduced tumour size was evident by MRI after five days of treatment (2Gy/day, 10Gy total dose). Immunohistochemical data from orthotopic patient-derived xenograft (PDX) models of Group 3- and Group 4-subgroup medulloblastomas indicate reduced sensitivity to radiation relative to the SHH model. These data serve as baseline information for future experimental protocols, incorporating combinatorial regimens of focal radiation, conventional chemotherapy and novel anti-cancer agents.
Transgenic and PDX mouse models are invaluable tools to evaluate new treatment protocols ahead of clinical trials. The XRAD SmART is a unique tool that accurately recapitulates clinical treatments in a preclinical setting, enabling more rigorous evaluation and selection of viable agents to consider for future clinical evaluation.