Intraventricular SHH inhibition proves efficient in SHH medulloblastoma mouse model and prevents systemic side effects.

Autor:	Kresbach C; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.; Center of Diagnostics, Institute of Neuropathology, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Mildred Scheel Cancer Career Center HaTriCS4, University Medical Center Hamburg- Eppendorf, Hamburg, Germany., Holst L; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Schoof M; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Leven T; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Göbel C; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Neyazi S; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Tischendorf J; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Loose C; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Wrzeszcz A; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany., Yorgan T; Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Rutkowski S; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany., Schüller U; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.; Research Institute Children's Cancer Center Hamburg, Hamburg, Germany.; Center of Diagnostics, Institute of Neuropathology, Center of Diagnostics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Jazyk:	angličtina
Zdroj:	Neuro-oncology [Neuro Oncol] 2024 Apr 05; Vol. 26 (4), pp. 609-622.
DOI:	10.1093/neuonc/noad191
Abstrakt:	Background: Medulloblastoma (MB) is the most common malignant brain tumor in children and requires intensive multimodal therapy. Long-term survival is still dissatisfying and, most importantly, survivors frequently suffer from severe treatment-associated morbidities. The sonic hedgehog pathway (SHH) in SHH MB provides a promising target for specific therapeutic agents. The small molecule Vismodegib allosterically inhibits SMO, the main upstream activator of SHH. Vismodegib has proven effective in the treatment of MB in mice and in clinical studies. However, due to irreversible premature epiphyseal growth plate fusions after systemic application to infant mice and children, its implementation to pediatric patients has been limited. Intraventricular Vismodegib application might provide a promising novel treatment strategy for pediatric medulloblastoma patients. Methods: Infant medulloblastoma-bearing Math1-cre::Ptch1Fl/Fl mice were treated with intraventricular Vismodegib in order to evaluate efficacy on tumor growth and systemic side effects. Results: We show that intraventricular Vismodegib treatment of Math1-cre::Ptch1Fl/Fl mice leads to complete or partial tumor remission only 2 days after completed treatment. Intraventricular treatment also significantly improved symptom-free survival in a dose-dependent manner. At the same time, intraventricular application prevented systemic side effects in the form of anatomical or histological bone deformities. Conclusions: We conclude that intraventricular application of a SHH pathway inhibitor combines the advantages of a specific treatment agent with precise drug delivery and might evolve as a promising new way of targeted treatment for SHH MB patients. (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
Databáze:	MEDLINE
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