The goals of this project are to advance understanding of the molecular pathogenesis of pediatric high grad glioma (HGG), identify targets for therapeutic intervention and generate improved model systems for biological study and pre-clinical testing. Pediatric HGGs comprise 15-20% of all pediatric CMS tumors, and carry an abysmal prognosis, with 70-90% of patients dying within 2 years of diagnosis. While the molecular genetics of adult HGG has been investigated extensively, much less is known about the pediatric disease, in large part due to limiting patient samples. The lack of tumor material for research is especially challenging for HGG arising in the pons, termed diffuse brainstem gliomas (BSG), because they are not treated surgically. A comprehensive high-resolution molecular analysis of a large collection of pediatric HGG has never been reported. Importantly, there are distinct differences in the frequency of specific gene mutations between pediatric and adult HGG, indicating that targeted therapeutic strategies developed for adults may not be optimal approaches for children. The foundation for our proposal includes novel in vitro and in vivo models for HGG developed during the first funding period, and a unique large collection of rare pediatric HGG samples for biological studies. We will complete a comprehensive high resolution analysis of pediatric HGG, identify candidate oncogenes and tumor suppressor genes for HGG and test their contribution to astrocytic tumorigenesis, and use novel mouse models to dissect tumor suppressor function in gliomagenesis in vivo. Our studies will be integrated with others in this program project to identify unique cancer pathways underlying pediatric HGG and common pathways leading to pediatric brain tumors.

Public Health Relevance

Up to 90% of children with high-grade glioma will die within 2 years of diagnosis. Our overall goal is to identify gene mutations that cause high-grade glioma in children and that can therefore act as targets for curative new therapies. We will also use and improve our existing model systems to test effects of these gene mutations and the ability of new therapeutic agents to stop glioma growth.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-GRB-S)
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St. Jude Children's Research Hospital
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Eden, C J; Ju, B; Murugesan, M et al. (2015) Orthotopic models of pediatric brain tumors in zebrafish. Oncogene 34:1736-42
Parker, Matthew; Mohankumar, Kumarasamypet M; Punchihewa, Chandanamali et al. (2014) C11orf95-RELA fusions drive oncogenic NF-?B signalling in ependymoma. Nature 506:451-5
Huether, Robert; Dong, Li; Chen, Xiang et al. (2014) The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat Commun 5:3630
Wu, Gang; Diaz, Alexander K; Paugh, Barbara S et al. (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46:444-50
Katyal, Sachin; Lee, Youngsoo; Nitiss, Karin C et al. (2014) Aberrant topoisomerase-1 DNA lesions are pathogenic in neurodegenerative genome instability syndromes. Nat Neurosci 17:813-21
Diaz, Alexander K; Baker, Suzanne J (2014) The genetic signatures of pediatric high-grade glioma: no longer a one-act play. Semin Radiat Oncol 24:240-7
Northcott, Paul A; Lee, Catherine; Zichner, Thomas et al. (2014) Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511:428-34
Lee, Youngsoo; Brown, Eric J; Chang, Sandy et al. (2014) Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss. J Neurosci 34:7836-44
Morfouace, Marie; Shelat, Anang; Jacus, Megan et al. (2014) Pemetrexed and gemcitabine as combination therapy for the treatment of Group3 medulloblastoma. Cancer Cell 25:516-29
Jones, Chris; Baker, Suzanne J (2014) Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma. Nat Rev Cancer 14:

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