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1.
Neuro Oncol ; 26(4): 609-622, 2024 04 05.
Article in English | MEDLINE | ID: mdl-37767814

ABSTRACT

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.


Subject(s)
Cerebellar Neoplasms , Medulloblastoma , Pyridines , Humans , Mice , Animals , Child , Medulloblastoma/drug therapy , Medulloblastoma/genetics , Medulloblastoma/metabolism , Hedgehog Proteins/metabolism , Anilides/pharmacology , Anilides/therapeutic use , Disease Models, Animal , Cerebellar Neoplasms/pathology
2.
Acta Neuropathol Commun ; 11(1): 174, 2023 11 02.
Article in English | MEDLINE | ID: mdl-37919824

ABSTRACT

Group 3 medulloblastoma is one of the most aggressive types of childhood brain tumors. Roughly 30% of cases carry genetic alterations in MYC, SMARCA4, or both genes combined. While overexpression of MYC has previously been shown to drive medulloblastoma formation in mice, the functional significance of SMARCA4 mutations and their suitability as a therapeutic target remain largely unclear. To address this issue, we combined overexpression of MYC with a loss of SMARCA4 in granule cell precursors. Both alterations did not increase proliferation of granule cell precursors in vitro. However, combined MYC overexpression and SMARCA4 loss successfully induced tumor formation in vivo after orthotopic transplantation in recipient mice. Resulting tumors displayed anaplastic histology and exclusively consisted of SMARCA4-negative cells although a mixture of recombined and non-recombined cells was injected. These observations provide first evidence for a tumor-promoting role of a SMARCA4 deficiency in the development of medulloblastoma. In comparing the transcriptome of tumors to the cells of origin and an established Sonic Hedgehog medulloblastoma model, we gathered first hints on deregulated gene expression that could be specifically involved in SMARCA4/MYC driven tumorigenesis. Finally, an integration of RNA sequencing and DNA methylation data of murine tumors with human samples revealed a high resemblance to human Group 3 medulloblastoma on the molecular level. Altogether, the development of SMARCA4-deficient medulloblastomas in mice paves the way to deciphering the role of frequently occurring SMARCA4 alterations in Group 3 medulloblastoma with the perspective to explore targeted therapeutic options.


Subject(s)
Brain Neoplasms , Cerebellar Neoplasms , Medulloblastoma , Animals , Humans , Mice , Brain Neoplasms/genetics , Cerebellar Neoplasms/metabolism , DNA Helicases/genetics , Hedgehog Proteins/metabolism , Medulloblastoma/metabolism , Nuclear Proteins/genetics , Nuclear Proteins/metabolism , Transcription Factors/genetics , Transcriptome
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