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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA096832-10
Application #
8459557
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$254,300
Indirect Cost
$85,553
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Pajtler, Kristian W; Wen, Ji; Sill, Martin et al. (2018) Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol 136:211-226
Teitz, Tal; Fang, Jie; Goktug, Asli N et al. (2018) CDK2 inhibitors as candidate therapeutics for cisplatin- and noise-induced hearing loss. J Exp Med 215:1187-1203
Tsang, Derek S; Burghen, Elizabeth; Klimo Jr., Paul et al. (2018) Outcomes After Reirradiation for Recurrent Pediatric Intracranial Ependymoma. Int J Radiat Oncol Biol Phys 100:507-515
Shadrick, William R; Slavish, Peter J; Chai, Sergio C et al. (2018) Exploiting a water network to achieve enthalpy-driven, bromodomain-selective BET inhibitors. Bioorg Med Chem 26:25-36
Roussel, Martine F; Stripay, Jennifer L (2018) Epigenetic Drivers in Pediatric Medulloblastoma. Cerebellum 17:28-36
Waszak, Sebastian M; Northcott, Paul A; Buchhalter, Ivo et al. (2018) Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort. Lancet Oncol 19:785-798
El Nagar, Salsabiel; Zindy, Frederique; Moens, Charlotte et al. (2018) A new genetically engineered mouse model of choroid plexus carcinoma. Biochem Biophys Res Commun 496:568-574
Nimmervoll, Birgit V; Boulos, Nidal; Bianski, Brandon et al. (2018) Establishing a Preclinical Multidisciplinary Board for Brain Tumors. Clin Cancer Res 24:1654-1666
Vo, BaoHan T; Kwon, Jin Ah; Li, Chunliang et al. (2018) Mouse medulloblastoma driven by CRISPR activation of cellular Myc. Sci Rep 8:8733
Enriquez-Rios, Vanessa; Dumitrache, Lavinia C; Downing, Susanna M et al. (2017) DNA-PKcs, ATM, and ATR Interplay Maintains Genome Integrity during Neurogenesis. J Neurosci 37:893-905

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