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MEK Inhibitors Reverse Growth of Embryonal Brain Tumors Derived from Oligoneural Precursor Cells
Katarzyna Modzelewska1, Elena F Boer1, Timothy L Mosbruger1
1Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
Abstract:
Malignant brain tumors are the leading cause of cancer-related deaths in children. Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are particularly aggressive embryonal tumors of unknown cellular origin. Recent genomic studies have classified CNS-PNETs into molecularly distinct subgroups that promise to improve diagnosis and treatment; however, the lack of cell- or animal-based models for these subgroups prevents testing of rationally designed therapies. Here, we show that a subset of CNS-PNETs co-express oligoneural precursor cell (OPC) markers OLIG2 and SOX10 with coincident activation of the RAS/MAPK (mitogen-activated protein kinase) pathway. Modeling NRAS activation in embryonic OPCs generated malignant brain tumors in zebrafish that closely mimic the human oligoneural/NB-FOXR2 CNS-PNET subgroup by histology and comparative oncogenomics. The zebrafish CNS-PNET model was used to show that MEK inhibitors selectively eliminate Olig2+/Sox10+ CNS-PNET tumors in vivo without impacting normal brain development. Thus, MEK inhibitors represent a promising rationally designed therapy for children afflicted with oligoneural/NB-FOXR2 CNS-PNETs.
Insights
Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are aggressive childhood brain cancers. A new zebrafish model shows MEK inhibitors effectively target a specific CNS-PNET subgroup, offering a promising new therapy.
Area of Science:
- Neuro-oncology
- Developmental Biology
- Genomics
Background:
- Malignant brain tumors cause significant childhood cancer mortality.
- Primitive neuroectodermal tumors of the CNS (CNS-PNETs) are aggressive embryonal tumors with unknown origins.
- Genomic classification reveals distinct CNS-PNET subgroups, but lack of models hinders therapeutic development.
Purpose of the Study:
- To develop a relevant preclinical model for CNS-PNETs.
- To identify potential therapeutic targets for CNS-PNET subgroups.
- To investigate the efficacy of MEK inhibitors in a CNS-PNET model.
Main Methods:
- Modeling NRAS activation in embryonic oligoneural precursor cells (OPCs) in zebrafish.
- Histological and comparative oncogenomic analysis of generated tumors.
- In vivo testing of MEK inhibitors on zebrafish CNS-PNET models.
Main Results:
- Zebrafish tumors recapitulated the human oligoneural/NB-FOXR2 CNS-PNET subgroup.
- The model demonstrated co-expression of OLIG2 and SOX10 with RAS/MAPK pathway activation.
- MEK inhibitors selectively eliminated CNS-PNET tumors in vivo without affecting normal brain development.
Conclusions:
- A zebrafish model accurately mimics a specific human CNS-PNET subgroup.
- MEK inhibitors show selective efficacy against Olig2+/Sox10+ CNS-PNETs.
- MEK inhibitors represent a promising targeted therapy for pediatric oligoneural/NB-FOXR2 CNS-PNETs.
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