PgmNr Z631: Zebrafish Pediatric Brain Tumor Modeling for Pre-clinical Drug Screening.

Authors:
R. Stewart 1 ; K. Modzelewska 1 ; E. Boer 1 ; R. Miles 1 ; J. Schiffman 1 ; A. Huang 2


Institutes
1) Huntsman Cancer Institute, University of Utah, Salt Lake City, UT; 2) Department of Pediatrics, Hospital for Sick Children, University of Toronto, ON, Canada.


Abstract:

Primitive Neuroectodermal Tumors (PNETs) represent the largest group of malignant brain tumors in children, with similar cellular histology but diverse clinical phenotypes/outcomes. The most common PNET is medulloblastoma located in the cerebellum, while more rare and aggressive PNET sub-groups located throughout the central nervous system (CNS) are collectively called CNS-PNETs. Due to the rarity of CNS-PNETs the cell of origin and oncogenic pathways driving their formation is not known, hindering development of targeted therapeutic options for these patients, who have an overall survival of ~ 20%. Recent genomic expression profiling has defined three CNS-PNETs subtypes: neural, oligoneural and mesenchymal. By modeling CNS-PNET gene signatures in zebrafish, we have generated the first animal model of oligoneural CNS-PNET. We show that activation of NRAS signaling in Sox10-expressing zebrafish embryonic cells with p53-deficiency generate oligoneural CNS-PNETs with conserved histological and molecular features to human CNS-PNETs, including activated MAPK/MEK signaling.  We have also performed orthotopic brain tumor transplantation and drug-screening assays to show MEK activity is essential for oligoneural CNS-PNET tumor growth in vivo, and survival of human PNET cells in vitro. Thus, MEK inhibitors represent the first targeted therapy option for children with oligoneural CNS-PNETs.



ZFIN Genetics Index
1. sox10
2. olig2