MEK Inhibitors Reverse Growth of Embryonal Brain Tumors Derived from Oligoneural Precursor Cells

作者：Modzelewska Katarzyna; Boer Elena F; Mo**ruger Timothy L; Picard Daniel; Anderson Daniela; Miles Rodney R; Kroll Mitchell; Oslund William; Pysher Theodore J; Schiffman Joshua D; Jensen Randy; Jette Cicely A; Huang Annie; Stewart Rodney A^*

来源：Cell Reports, 2016, 17(5): 1255-1264.

DOI：10.1016/j.celrep.2016.09.081

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 closelymimic 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.

• 出版日期2016-10-25