title: MEK Inhibitors Reverse Growth of Embryonal Brain Tumors Derived from Oligoneural Precursor Cells.
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.
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Katarzyna
authors: K
authors: Modzelewska
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Elena F
authors: EF
authors: Boer
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Timothy L
authors: TL
authors: Mosbruger
authors: Division of Hematology-Oncology, Arthur and Sonia Labatt Brain Tumour Research Centre, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M4N1X8, Canada.
authors: Daniel
authors: D
authors: Picard
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Daniela
authors: D
authors: Anderson
authors: Department of Pathology and ARUP Laboratories, University of Utah, 500 Chipeta Way, Salt Lake City, UT 84108, USA.
authors: Rodney R
authors: RR
authors: Miles
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Mitchell
authors: M
authors: Kroll
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: William
authors: W
authors: Oslund
authors: Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Primary Children's Hospital/Intermountain Healthcare, Salt Lake City, UT 84113, USA.
authors: Theodore J
authors: TJ
authors: Pysher
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA; Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Joshua D
authors: JD
authors: Schiffman
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Randy
authors: R
authors: Jensen
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
authors: Cicely A
authors: CA
authors: Jette
authors: Division of Hematology-Oncology, Arthur and Sonia Labatt Brain Tumour Research Centre, Department of Pediatrics, Hospital for Sick Children, University of Toronto, Toronto, ON M4N1X8, Canada.
authors: Annie
authors: A
authors: Huang
authors: Department of Oncological Sciences and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA. Electronic address: rodney.stewart@hci.utah.edu.
authors: Rodney A
authors: RA
authors: Stewart
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004353:Drug Evaluation, Preclinical; D020558:GTP Phosphohydrolases / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D016678:Genome; D020935:MAP Kinase Signaling System; D008565:Membrane Proteins / Q000378:metabolism; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009373:Neoplasms, Germ Cell and Embryonal / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D018242:Neuroectodermal Tumors, Primitive / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D009857:Oncogenes; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism*; D015027:Zebrafish
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: CNS-PNET; MAPK; MEK inhibitors; OLIG2; RAS; SOX10; embryonal; oligodendrocyte; pediatric brain tumors; zebrafish