Glioblastoma Multiforme (GBM) is an aggressive malignant brain cancer with high mortality rates. Recent evidence suggests that GBM arise from adult human neural stem cells (NSCs). Support for this hypothesis comes from mouse models of glioma and from work demonstrating the presence of neural stem-like cells within primary brain tumors. These tumor stem cells (TSCs) maintain the aggressive phenotype of GBM due to their enhanced proliferation, motility, invasion and survival. The precise mechanism for human GBM aggressiveness is currently not known although activated Epidermal Growth Factor Receptor (EGFR) signaling is thought to be a contributing factor. Previous studies have shown that elevated EGFR signaling enhances the tumorigenicity of GBM by increasing resistance to both radiation and chemotherapy. However, there have been no studies evaluating the precise role of activated EGFR signaling in adult SVZ precursors or in GBM-derived TSCs. Therefore, the proposed experiments are designed to test the hypothesis that activated EGFR signals in adult SVZ precursors contributes to a motile, proliferative and survival phenotype and that enhanced EGFR signals in TSCs contributes to the malignant phenotype of GBM. We will address these hypotheses in the following testable aims: 1. determine the role of activated EGFR signaling in normal adult NSC proliferation, motility and survival; 2. elucidate the contribution of EGFR signaling to the tumorigenicity of TSCs in GBM; 3. to define downstream components that play a role in modulating the impact of upstream EGFR activation. Our studies using normal murine and human adult NSCs will allow for increased understanding of the basic biology of adult NSCs. This will have importance in elucidating the 'cell-of-origin'in GBM and may help explain how EGFR enhances NSC survival, which is relevant to tumor resistance to current treatment strategies. The studies involving TSCs will be important for accurate modeling of GBM and for preclinical studies using targeted therapies personalized to each patient based on the characteristics of their TSC subpopulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA130985-05
Application #
8318263
Study Section
Subcommittee G - Education (NCI)
Program Officer
Perkins, Susan N
Project Start
2008-09-15
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$136,890
Indirect Cost
$10,140
Name
Weill Medical College of Cornell University
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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