PUBLICATION
MEK Inhibitors Reverse Growth of Embryonal Brain Tumors Derived from Oligoneural Precursor Cells
- Authors
- Modzelewska, K., Boer, E.F., Mosbruger, T.L., Picard, D., Anderson, D., Miles, R.R., Kroll, M., Oslund, W., Pysher, T.J., Schiffman, J.D., Jensen, R., Jette, C.A., Huang, A., Stewart, R.A.
- ID
- ZDB-PUB-161027-2
- Date
- 2016
- Source
- Cell Reports 17: 1255-1264 (Journal)
- Registered Authors
- Boer, Elena, Jette, Cicely A., Modzelewska, Kate, Stewart, Rodney A.
- Keywords
- CNS-PNET, MAPK, MEK inhibitors, OLIG2, RAS, SOX10, embryonal, oligodendrocyte, pediatric brain tumors, zebrafish
- Datasets
- GEO:GSE80768
- MeSH Terms
-
- Animals
- Biomarkers, Tumor/metabolism
- Brain Neoplasms/drug therapy
- Brain Neoplasms/genetics
- Brain Neoplasms/pathology*
- Drug Evaluation, Preclinical
- GTP Phosphohydrolases/metabolism
- Gene Expression Profiling
- Gene Expression Regulation, Neoplastic/drug effects
- Genome
- MAP Kinase Signaling System
- Membrane Proteins/metabolism
- Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors*
- Mitogen-Activated Protein Kinase Kinases/metabolism
- Neoplasms, Germ Cell and Embryonal/drug therapy
- Neoplasms, Germ Cell and Embryonal/genetics
- Neoplasms, Germ Cell and Embryonal/pathology*
- Neuroectodermal Tumors, Primitive/drug therapy
- Neuroectodermal Tumors, Primitive/genetics
- Neuroectodermal Tumors, Primitive/pathology*
- Oncogenes
- Protein Kinase Inhibitors/pharmacology*
- Protein Kinase Inhibitors/therapeutic use
- Stem Cells/drug effects
- Stem Cells/metabolism*
- Zebrafish
- PubMed
- 27783941 Full text @ Cell Rep.
Citation
Modzelewska, K., Boer, E.F., Mosbruger, T.L., Picard, D., Anderson, D., Miles, R.R., Kroll, M., Oslund, W., Pysher, T.J., Schiffman, J.D., Jensen, R., Jette, C.A., Huang, A., Stewart, R.A. (2016) MEK Inhibitors Reverse Growth of Embryonal Brain Tumors Derived from Oligoneural Precursor Cells. Cell Reports. 17:1255-1264.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping