? Project 1 The goals of this project are to advance understanding of the pathogenesis of pediatric high-grade glioma (HGG), define connections between neural development and gliomagenesis, and generate improved model systems with specific relevance to pediatric HGG. Pediatric HGGs comprise 15-20% of all pediatric CNS tumors, and remain largely incurable, with a two year survival rate of less than 30%. A subset of pediatric HGGs arise within the brainstem as diffuse intrinsic pontine glioma (DIPG), a tumor that arises almost exclusively in children with a two year survival of less than 10%. During the last funding period, we developed improved mouse models of HGG, and conducted in-depth genome-wide studies of pediatric HGG including DIPG. Results from our group and others showed distinct differences in the genetic alterations driving childhood and adult HGG. Most strikingly, recurrent somatic mutations in histone H3 are found in 78% of DIPGs and 36% of HGGs, but only rarely in young adults with glioblastoma, and not in older adult glioblastoma patients. Building on this progress, we propose to determine why histone H3 mutations have a unique selective advantage in the context of developing brain, to determine their contribution to tumorigenesis and the epigenomic landscape of pediatric HGG, and to develop improved model systems of pediatric HGG for biological studies and preclinical testing. Our studies are integrated with those in the other projects that explore mechanisms and genetic and epigenetic signatures driving glioma and medulloblastoma formation, and the identification of therapeutic targets for these devastating diseases. The project receives essential support from the Bioinformatics and Neuropathology Cores for the complex integrated analysis of molecular and histopathological features of tumors generated in model systems and comparisons with primary human tumors.

Public Health Relevance

? Project 1 More than 70% of children with high-grade glioma will die within two years of their diagnosis. Our overall goal is to understand how the frequent mutations that we identified in pediatric high-grade glioma contribute to the development of the disease, and how these effects can be counteracted to develop improved therapeutic approaches for these devastating childhood brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA096832-12
Application #
9149700
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
12
Fiscal Year
2016
Total Cost
Indirect Cost
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
Hoch, Nicolas C; Hanzlikova, Hana; Rulten, Stuart L et al. (2017) XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia. Nature 541:87-91

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