Ependymoma (EPN), the third most common brain tumor of pediatrics, is treated by surgical removal and radiation therapy. Unfortunately, more than 50% of children with EPN will suffer from tumor recurrence, which will ultimately result in death. Despite the severity of this disease, little progress has been made in identification of factors underlying EPN recurrence. The long-term goal of my research addresses this urgent need by searching more effective prognostic markers for EPN and elucidating EPN biological information that could facilitate development of more effective therapies. Recent microarray gene expression studies by my laboratory revealed that the predominant feature that distinguishes EPN from children whose tumor did not recur versus those whose did is an overexpression of immune response related genes. These results suggest that a host anti-tumor immune response in EPN, when combined with standard therapy, results in complete eradication of the remaining residual tumor cells. My central hypothesis is that detailed characterization of the immune related genes associated with good clinical outcome in EPN will simultaneously (a) provide an accurate prognostic marker for EPN, and (b) provide critical knowledge of the interaction between the human immune system and CNS tumors that will aid our understanding of host tumor control. Progress on either of these fronts would benefit clinical trials in childhood EPN.
The specific aims of my research proposal are (i) retrospective global gene and protein expression analysis of frozen tumor specimens, (ii) retrospective histological analysis of candidate immune cells and molecules in paraffin embedded and frozen tumor, and (iii) prospective analysis of tumor-infiltrating and peripheral immune cells using fresh surgical samples. The results of these studies will potentially solve the clinical problem of how to identify those children with EPN who will recur, which will allow us to better focus patient selection for clinical trials. In addition to this, and with a wider importance to immunotherapy of tumors in the CNS and elsewhere, is the characterization of the putative host anti-tumor immune response that we have identified in good outcome associated EPN. Previous CNS tumor immunotherapeutic strategies, largely based on the results of animal models, have shown limited success. The proposed research may overcome this barrier by advancing our overall understanding of how the body naturally initiates and effects an immune response against CNS tumors in humans, rather than the approximation of this previously afforded by such animal models. This knowledge could then be used to improve therapy for those children with a likelihood of EPN recurrence, with potential application in other CNS malignancies.

Public Health Relevance

Most people with brain tumors die. We have found an immune response in a type of childhood brain tumor called an ependymoma. We wish to explore whether this immune response can be used to cure ependymomas and potentially other brain tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140614-04
Application #
8403552
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Lively, Tracy (LUGO)
Project Start
2010-03-17
Project End
2013-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
4
Fiscal Year
2013
Total Cost
$289,474
Indirect Cost
$100,275
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Hoffman, Lindsey M; Donson, Andrew M; Nakachi, Ichiro et al. (2014) Molecular sub-group-specific immunophenotypic changes are associated with outcome in recurrent posterior fossa ependymoma. Acta Neuropathol 127:731-45
Griesinger, Andrea M; Birks, Diane K; Donson, Andrew M et al. (2013) Characterization of distinct immunophenotypes across pediatric brain tumor types. J Immunol 191:4880-8