The recent discovery that many cancers are generated by small fractions cancer stem cells (CSC) suggests that targets of effective new treatments might be found among the mutations that initiate and maintain these cells. Ependymomas include a diverse group of tumors that arise throughout the central nervous system (CNS) of children and adults. These tumors often resist conventional treatments and are incurable in up to 40% of patients. Therefore, to identify potential new therapeutic approaches for ependymoma, we sort to identify the cell(s) of origin of this disease and the mutations that transform these into CSC. By comparing the gene expression profiles of tumors with those of the developing nervous system, we found that ependymomas from the different parts of the CNS share the gene expression profiles of neural precursor cells, termed radial glia (RG), in the corresponding region of the embryonic nervous system. We showed also that ependymomas are propagated and maintained by CSC that are remarkably similar to RG and that ependymomas from the different parts of the CNS contain anatomic site-specific chromosomal alterations. Thus, we hypothesize that RG in the different parts of the CNS are cells of origin of ependymoma and are predisposed to acquire distinct gene mutations that transform these cells into ependymoma CSC. To test our hypothesis we propose a series of highly-integrated genomic and CSC studies that will employ mouse models and the largest cohort of human ependymoma tumors collated to date. We propose to: 1) Use the 500K single nucleotide polymorphism mapping array profiles that we have generated already from 230 samples of ependymoma to identify candidate oncogenes and tumor suppressor genes (TSG) of this disease. 2) Activate candidate oncogenes and knock-down candidate TSG in RG from the different regions of the CNS to determine if these cells are susceptible to be transformed into CSC. Assessment of CSC properties will include unbridled self-renewal and tumor initiating capacity. 3) Engineer in RG of a genetic mouse model, concurrent activation of Notchl signaling and Ink4a/Arf deletion that we have observed in human intracranial ependymoma. Relevance to Public Health: There is a desperate need for effective new treatments of ependymoma. By defining the cell of origin of ependymoma and the mutations that transform these cells, the Aims of this proposal will bring about a profound increase in understanding of this disease and identify molecular targets for new treatments.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129541-04
Application #
7813962
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Watson, Joanna M
Project Start
2007-07-01
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$319,200
Indirect Cost
Name
St. Jude Children's Research Hospital
Department
Type
DUNS #
067717892
City
Memphis
State
TN
Country
United States
Zip Code
38105
Morfouace, Marie; Nimmervoll, Birgit; Boulos, Nidal et al. (2016) Preclinical studies of 5-fluoro-2'-deoxycytidine and tetrahydrouridine in pediatric brain tumors. J Neurooncol 126:225-34
Phoenix, Timothy N; Patmore, Deanna M; Boop, Scott et al. (2016) Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype. Cancer Cell 29:508-522
Eden, C J; Ju, B; Murugesan, M et al. (2015) Orthotopic models of pediatric brain tumors in zebrafish. Oncogene 34:1736-42
Robinson, Giles W; Orr, Brent A; Wu, Gang et al. (2015) Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol 33:2646-54
Patel, Yogesh T; Jacus, Megan O; Boulos, Nidal et al. (2015) Preclinical examination of clofarabine in pediatric ependymoma: intratumoral concentrations insufficient to warrant further study. Cancer Chemother Pharmacol 75:897-906
Tong, Yiai; Merino, Diana; Nimmervoll, Birgit et al. (2015) Cross-Species Genomics Identifies TAF12, NFYC, and RAD54L as Choroid Plexus Carcinoma Oncogenes. Cancer Cell 27:712-27
Hoffman, Lindsey M; Fouladi, Maryam; Olson, James et al. (2015) Phase I trial of weekly MK-0752 in children with refractory central nervous system malignancies: a pediatric brain tumor consortium study. Childs Nerv Syst 31:1283-9
Wright, Karen D; Daryani, Vinay M; Turner, David C et al. (2015) Phase I study of 5-fluorouracil in children and young adults with recurrent ependymoma. Neuro Oncol 17:1620-7
Pajtler, Kristian W; Witt, Hendrik; Sill, Martin et al. (2015) Molecular Classification of Ependymal Tumors across All CNS Compartments, Histopathological Grades, and Age Groups. Cancer Cell 27:728-43
Kilburn, Lindsay B; Kocak, Mehmet; Decker, Rodney L et al. (2015) A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study. Neuro Oncol 17:303-11

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