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

Abstract

Medulloblastoma (MB) is the most common malignant paediatric brain tumour, 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 normal brain has deleterious consequences to neurocognitive and physical functioning, and causes accelerated ageing/frailty. Approaches to ameliorate radiotherapy-induced late-effects are lacking and a paucity of appropriate model systems hinders their development. 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 CT image-guided CRT (human-equivalent 37.5 Gy EQD2, n=12) ± PFB (human-equivalent 48.7 Gy EQD2, n=12), via the small animal radiation research platform (SARRP) and were longitudinally assessed for >12 months. CRT was well tolerated, independent of PFB receipt. Compared to a sham-irradiated group (n=12), irradiated mice were significantly frailer following irradiation (frailty index; p=0.0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; p=0.026) and grip strength (p=0.006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; p=0.009) and exhibited spatial memory deficits (Barnes maze; p=0.029). Receipt of PFB did not induce a more severe late-effect profile. 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.