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

Neuroectodermal Tumors, Primitive/drug therapy
Neuroectodermal Tumors, Primitive/genetics
Neuroectodermal Tumors, Primitive/pathology*
Animals
Zebrafish
Membrane Proteins/metabolism
Oncogenes
Biomarkers, Tumor/metabolism
Gene Expression Profiling
Drug Evaluation, Preclinical
GTP Phosphohydrolases/metabolism
Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors*
Mitogen-Activated Protein Kinase Kinases/metabolism
MAP Kinase Signaling System
Neoplasms, Germ Cell and Embryonal/drug therapy
Neoplasms, Germ Cell and Embryonal/genetics
Neoplasms, Germ Cell and Embryonal/pathology*
Genome
Gene Expression Regulation, Neoplastic/drug effects
Stem Cells/drug effects
Stem Cells/metabolism*
Brain Neoplasms/drug therapy
Brain Neoplasms/genetics
Brain Neoplasms/pathology*
Protein Kinase Inhibitors/pharmacology*
Protein Kinase Inhibitors/therapeutic use

PubMed

27783941 Full text @ Cell Rep.

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

Figures