Ependymomas are tumors of the brain and spinal cord. Treatment approaches and mortality rates for this disease have changed little over the last twenty years, highlighting the great need for new therapies. Histologic similarities among ependymomas have led investigators to treat these tumors as a single entity;but we have shown that ependymomas from different regions of the central nervous system include discrete clinical and molecular subtypes, suggesting they are different diseases. Thus, contemporary efforts to cure all patients with ependymoma must be concerned with understanding the biological basis of these disease subtypes, and where necessary, developing subtype-specific therapies. During the last funding cycle we developed a cross- species genomics approach that characterized genomic subtypes of human ependymoma and matched these with neural stem cells in the mouse to generate accurate models of the disease. We will build on this work to complete three Specific Aims designed to test the central hypothesis that 'Ependymoma subtypes are driven by distinct cell signals that can be targeted for therapeutic gain.'Aim 1 will employ new 'virus-pool'screens to test the in vivo oncogenic role of the top 90 candidate oncogenes and 40 tumor suppressor genes that we previously identified in ependymoma. We will thereby generate a 'clinic'of mice that recapitulate the full spectrum on human ependymoma subtypes.
Aim 2 will interrogate the models developed in Aim 1 using high- throughput drug screens, kinome-wide binding and cell biology assays to pinpoint the key cell signals that maintain each ependymoma subtype that might therefore serve as therapeutic targets. Integration of these data with genetic analyses of human and mouse tumors will further validate candidate drug targets. Future clinical trials of therapies that target signals identified in Aim 2 will demand the selection of patients with the appropriate disease subtype. Therefore, Aim 3 will develop a robust Affymetrix Quantigene assay to reliably and rapidly diagnose ependymoma subtypes using formalin fixed paraffin embedded tissue.

Public Health Relevance

The failure to progress the treatment of patients with ependymoma has resulted from a lack of preclinical models and a drug development process that does not account for the discrete subtypes that comprise the disease. Our proposal will develop highly accurate mouse models of the full spectrum of ependymoma and use these to identify robust drug targets and diagnostic tools for subtype-specific clinical trials.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA129541-06
Application #
8319826
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Mietz, Judy
Project Start
2007-07-01
Project End
2017-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
6
Fiscal Year
2012
Total Cost
$322,525
Indirect Cost
$138,225
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
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
Gururangan, Sridharan; Fangusaro, Jason; Poussaint, Tina Young et al. (2014) Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor Consortium study. Neuro Oncol 16:310-7
Northcott, Paul A; Lee, Catherine; Zichner, Thomas et al. (2014) Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma. Nature 511:428-34
Pawlikowska, Iwona; Wu, Gang; Edmonson, Michael et al. (2014) The most informative spacing test effectively discovers biologically relevant outliers or multiple modes in expression. Bioinformatics 30:1400-8
Lehtinen, Maria K; Bjornsson, Christopher S; Dymecki, Susan M et al. (2013) The choroid plexus and cerebrospinal fluid: emerging roles in development, disease, and therapy. J Neurosci 33:17553-9
Taylor, Michael D; Northcott, Paul A; Korshunov, Andrey et al. (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465-72
Pounds, Stan; Gao, Cuilan Lani; Johnson, Robert A et al. (2011) A procedure to statistically evaluate agreement of differential expression for cross-species genomics. Bioinformatics 27:2098-103
Gilbertson, Richard J (2011) Mapping cancer origins. Cell 145:25-9
Lindsey, Janet C; Hill, Rebecca M; Megahed, Hisham et al. (2011) TP53 mutations in favorable-risk Wnt/Wingless-subtype medulloblastomas. J Clin Oncol 29:e344-6; author reply e347-8

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