- Project 2 Brain tumors are the most common solid malignancies of childhood and are a leading cause of cancer-related death in children. 15-20% of pediatric CNS tumors are high-grade gliomas (HGG), and individuals with these tumors have a 2-year survival rate of 10-30%. Despite extensive research into the molecular basis of gliomagenesis, current therapies remain ineffective, and the majority of patients die from their disease. More effective therapeutic strategies are likely to come from a detailed understanding of glioma pathogenesis. We have developed a unique series of new HGG mouse models, relevant to the human disease, which are characterized by a range of histopathology reflective of the specific defect in the DNA damage response.
In Aim 1 of this proposal we will determine the genomic alterations and gene expression profiles that underpin these gliomas, particularly in the context of human disease and other mouse glioma models, either established or under development in other projects in this program. We will also determine the basis for tumor heterogeneity in these models by ascertaining the detailed developmental origins of these gliomas and the relative susceptibility of different neural progenitors to transformation. These analyses will illuminate critical aspects of the pathogenesis of gliomas for which there is a paucity of definitive information. Finally, we will also determine cooperativity in these models with other mutations found in human pediatric HGG, including histone H3 mutations, taking advantage of novel models generated by other projects within the program.
In Aim 2 we propose experiments to establish which DNA repair pathways are critical for genome stability at different cortical progenitor stages and how this is linked to chromatin. Because histone mutations and other epigenetic alterations have recently been identified as causative molecular changes in pediatric HGG, our study will be of central importance for understanding connections between DNA damage signaling, epigenetics and tumorigenesis.
In Aim 3 we will determine if DNA breaks associated with early replicating fragile sites account for DNA structural alterations central to gliomagenesis. Collectively, findings from this study will provide fundamental new information to delineate glioma biology that will be important for developing targeted therapy for these diseases.

Public Health Relevance

? Project 2 The majority of glioma patients die from their disease. More effective therapeutic strategies to treat these tumors are likely to come from a deeper understanding of glioma pathogenesis. We propose using a novel series of new mouse glioma models to understand the detailed developmental origins of these tumors and how different neural progenitors are susceptible to transformation. Our findings to uncover the cellular and molecular basis for glioma heterogeneity will be important for developing targeted therapeutic strategies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA096832-15
Application #
9697358
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
15
Fiscal Year
2019
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
Mackay, Alan; Burford, Anna; Carvalho, Diana et al. (2017) Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma. Cancer Cell 32:520-537.e5

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