Brain tumors are the most common group of solid malignancies in children, causing devastating mortality and morbidity in an understudied patient population. The goal of this program project is to improve understanding and treatment of pediatric high-grade glioma and medulloblastoma. During the last funding period, Project Leaders worked together to develop novel mouse models that provided key biological insights into normal and tumorigenic growth in the brain, used these models for preclinical testing of new therapeutic agents, and translated research results into clinical trials. Whole genome sequencing efforts also provided an unprecedented view of the genomic landscape of pediatric high-grade glioma and medulloblastoma, including newly identified recurrent mutations, some of which impact epigenetic regulation. The current proposal builds on these exciting findings, with four highly interactive projects that plan state-of-the-art approaches to determine the mechanisms through which genetic and epigenetic alterations drive tumorigenesis in the developing brain. An Administrative Core, a Bioinformatics Core, and a Neuropathology Core provide essential support to all projects. In Project 1, S Baker will investigate connections between neural development, gliomagenesis and epigenetic regulation, with a focus on recurrent histone H3 mutations found in pediatric high-grade glioma. In Project 2, P McKinnon will employ new mouse models of glioma to define critical connections between the DNA damage response in neural progenitors, replication stress, and tumorigenesis. In Project 3, M Roussel will extend her progress in developing a mouse model for the Group 3 subgroup of medulloblastoma to determine the connections between epigenetic regulation and MYC signaling in medulloblastoma tumorigenesis, and to identify small molecules targeting epigenetic modifiers that inhibit Group 3 medulloblastoma. In Project 4, R Gilbertson will build upon his success in defining and modeling medulloblastoma subtypes to determine the role of specific mutations in hindbrain development and medulloblastoma, and to develop and test subtype-specific therapies in preclinical models.

Public Health Relevance

- Overview Pediatric brain tumors cause devastating mortality and morbidity, and are understudied. This program will continue to advance understanding of the mechanisms driving pediatric high-grade glioma and medulloblastoma, to identify new therapeutic targets and to explore the mechanisms of action of promising therapeutic agents. Previous successes of this program include the identification of key mutations driving these childhood brain tumors, and translation of basic research findings into new clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA096832-12
Application #
9095215
Study Section
Special Emphasis Panel (ZCA1)
Project Start
2002-07-01
Project End
2020-05-31
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
Wei, Lei; Murphy, Brian L; Wu, Gang et al. (2017) Exome sequencing analysis of murine medulloblastoma models identifies WDR11 as a potential tumor suppressor in Group 3 tumors. Oncotarget 8:64685-64697

Showing the most recent 10 out of 208 publications