In vivo modeling recapitulates radiotherapy delivery and late-effect profile for childhood medulloblastoma.

Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, with 5-year survival rates > 70%. Cranial radiotherapy (CRT) to the whole brain, with posterior fossa boost (PFB), underpins treatment for non-infants; however, radiotherapeutic insult to the normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated aging/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development.

Methods: We have developed a clinically relevant in vivo model system that recapitulates the radiotherapy dose, targeting, and developmental stage of childhood medulloblastoma. Consistent with human regimens, age-equivalent (postnatal days 35-37) male C57Bl/6J mice received computerized tomography image-guided CRT (human-equivalent 37.5 Gy EQD2,  = 12) ± PFB (human-equivalent 48.7 Gy EQD2,  = 12), via the small animal radiation research platform and were longitudinally assessed for > 12 months.

Results: CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group ( = 12), irradiated mice were significantly frailer following irradiation (frailty index;  = .0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod;  = .026) and grip strength ( = .006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze;  = .009) and exhibited spatial memory deficits (Barnes maze;  = .029). Receipt of PFB did not induce a more severe late-effect profile.

Conclusions: Our in vivo model mirrored childhood MB radiotherapy and recapitulated features observed in the late-effect profile of MB survivors. Our clinically relevant model will facilitate both the elucidation of novel/target mechanisms underpinning MB late effects and the development of novel interventions for their amelioration.