Malignant astrocytomas are among the most common and deadly brain tumors of childhood. Most affected children die within several years of diagnosis, despite current treatments;however, 20 to 30% respond favorably to therapy and are cured. The basis for these diverse outcomes has been enigmatic, even taking into account clinical and histological factors. In preliminary studies with an institutional cohort of pediatric gliomas, we observed that molecular markers could supplement histological data to refine prognostic assessments. Based on these findings, we began a more extensive study of the cohort of Children's Cancer Group study CCG-945, the largest group of pediatric high-grade gliomas accrued to date, and subsequently the Children's Oncology Group ACNS0126 study. During the previous funding period of this project, archival tumor specimens were obtained on more than 230 patients, the vast majority of which were evaluable in histological and genotyping analyses, the largest such analyses undertaken to date. The large size of these cohorts and the consistent treatment approaches used, coupled with the availability of central neuropathology review and comprehensive clinical data, provided a unique opportunity to address issues of molecular etiology and prognostic factors. Our studies demonstrated a striking association between outcome and several molecular features, including MGMT expression status, independent of clinical or histological factors;identified significant differences between molecular features of childhood and adult gliomas;and generated a sizeable resource of tumor tissue for further analyses. The proposed studies will use this resource as well as newly acquired tumor specimens and paired normal tissue, derived from 200 children treated on two new Children's Oncology Group high-grade glioma studies, to define the genetic alterations that characterize pediatric malignant gliomas, as a basis for prioritizing novel targets for prognostic and therapeutic stratification. We hypothesize that categorization of these tumors by their genomic alterations and drug resistance phenotype will improve accuracy of diagnostic and prognostic assessments, and provide insights into novel therapeutic targets. To test these hypotheses, we propose studies with the following aims: 1) Assess the frequency, composition, and prognostic relevance of alterations in Akt and MAPK pathway activation in pediatric malignant gliomas;2) Determine whether O6-methylguanine- DNA methyltransferase (MGMT) overexpression and promoter methylation are associated with progression- free survival, independent of alkylator therapy;3) Define, on a genome-wide basis, the spectrum and prognostic relevance of genomic alterations in pediatric malignant gliomas, using high-density SNP microarray- based profiling. Relevant markers will be evaluated in the context of conventional prognostic factors, such as histology, to determine their utility for biologically classifying childhood malignant gliomas.

Public Health Relevance

Taken together, the proposed studies will incorporate a unique resource of childhood malignant brain tumor samples to provide new insights into the molecular categorization of pediatric high-grade gliomas. This work will establish a foundation for risk-adapted stratification and treatment planning, and the design of future therapeutic strategies for children with these tumors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS037704-13
Application #
8225135
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Fountain, Jane W
Project Start
1998-09-01
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
13
Fiscal Year
2012
Total Cost
$333,121
Indirect Cost
$104,244
Name
University of Pittsburgh
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Jakacki, Regina I; Cohen, Kenneth J; Buxton, Allen et al. (2016) Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study. Neuro Oncol 18:1442-50
Nikiforova, Marina N; Wald, Abigail I; Melan, Melissa A et al. (2016) Targeted next-generation sequencing panel (GlioSeq) provides comprehensive genetic profiling of central nervous system tumors. Neuro Oncol 18:379-87
Bouffet, Eric; Allen, Jeffrey C; Boyett, James M et al. (2016) The influence of central review on outcome in malignant gliomas of the spinal cord: the CCG-945 experience. J Neurosurg Pediatr 17:453-9
Eisenstat, David D; Pollack, Ian F; Demers, Alain et al. (2015) Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children's Cancer Group high-grade glioma study CCG-945. J Neurooncol 121:573-81
Batra, Vandana; Sands, Stephen A; Holmes, Emi et al. (2014) Long-term survival of children less than six years of age enrolled on the CCG-945 phase III trial for newly-diagnosed high-grade glioma: a report from the Children's Oncology Group. Pediatr Blood Cancer 61:151-7
Mao, Ping; Joshi, Kaushal; Li, Jianfeng et al. (2013) Mesenchymal glioma stem cells are maintained by activated glycolytic metabolism involving aldehyde dehydrogenase 1A3. Proc Natl Acad Sci U S A 110:8644-9
Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2013) Ependymomas: development of immunotherapeutic strategies. Expert Rev Neurother 13:1089-98
Joshi, Kaushal; Banasavadi-Siddegowda, Yeshavanth; Mo, Xiaokui et al. (2013) MELK-dependent FOXM1 phosphorylation is essential for proliferation of glioma stem cells. Stem Cells 31:1051-63
Horbinski, Craig; Nikiforova, Marina N; Hagenkord, Jill M et al. (2012) Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro Oncol 14:777-89
Pollack, Ian F; Hamilton, Ronald L; Sobol, Robert W et al. (2011) IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group. Childs Nerv Syst 27:87-94

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