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

Autor:	Castle J; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Shaw G; Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James's University Hospital, Beckett St, Leeds, UK., Weller D; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Fielder E; Biosciences Institute, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK., Egnuni T; Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James's University Hospital, Beckett St, Leeds, UK., Singh M; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Skinner R; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., von Zglinicki T; Biosciences Institute, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK., Clifford SC; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK., Short SC; Leeds Institute of Medical Research, Wellcome Trust Brenner Building, St James's University Hospital, Beckett St, Leeds, UK., Miwa S; Biosciences Institute, Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, UK., Hicks D; Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2024 Jun 06; Vol. 6 (1), pp. vdae091. Date of Electronic Publication: 2024 Jun 06 (Print Publication: 2024).
DOI:	10.1093/noajnl/vdae091
Abstrakt:	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. Competing Interests: The authors have no conflicts of interest to declare. (© The Author(s) 2024. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Databáze:	MEDLINE
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