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

Lookup NU author(s): Dr Jemma CastleORCiD, Dr Edward FielderORCiD, Mankaran Singh, Professor Roderick Skinner, Professor Thomas von Zglinicki, Professor Steven CliffordORCiD, Dr Satomi MiwaORCiD, Dr Debbie HicksORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2024 The Author(s). Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. 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, n = 12) ± PFB (human-equivalent 48.7 Gy EQD2, n = 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 (n = 12), irradiated mice were significantly frailer following irradiation (frailty index; P = .0002) and had reduced physical functioning; time to fall from a rotating rod (rotarod; P = .026) and grip strength (P = .006) were significantly lower. Neurocognitive deficits were consistent with childhood MB survivors; irradiated mice displayed significantly worse working memory (Y-maze; P = .009) and exhibited spatial memory deficits (Barnes maze; P = .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.

Publication metadata

Author(s): Castle J, Shaw G, Weller D, Fielder E, Egnuni T, Singh M, Skinner R, Von Zglinicki T, Clifford SC, Short SC, Miwa S, Hicks D

Publication type: Article

Publication status: Published

Journal: Neuro-Oncology Advances

Year: 2024

Volume: 6

Issue: 1

Online publication date: 06/06/2024

Acceptance date: 02/04/2018

Date deposited: 17/07/2024

ISSN (electronic): 2632-2498

Publisher: Oxford University Press

URL: https://doi.org/10.1093/noajnl/vdae091

DOI: 10.1093/noajnl/vdae091

Data Access Statement: The data that support the study’s findings are available from the corresponding author (DH) upon reasonable request.

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