The prognosis for patients with malignant astrocytic tumors is poor. The capacity of astrocytomas both to invade adjacent brain sites and to migrate into distant ones precludes curative surgical resection;and little progress has been made in designing adjuvant therapies that significantly affect long-term survival. In order to formulate more novel therapeutic strategies, it is essential to have a better understanding of how the invasive growth of these tumors is controlled. Our animal model and in vitro results suggest that even though PKC-eta expression increases mitogenic response, the glioblastoma cells are less invasive. Our working hypothesis is: Expression and activation of PKC-eta decrease astrocytic tumor invasion.
Three aims are proposed to test the hypothesis (I) To determine the factors controlling the expression of PKC-eta in astrocytic tumor cells (II) To determine the role and mechanism of PKC-eta-mediated decrease in glioblastoma invasion in vitro and (III) To assess the role of PKC-eta expression on GBM invasive growth in a xenograft GBM NOD- SCID mouse model using immunohistochemistry, tissue slice migration and magnetic resonance imaging (MRI).

Public Health Relevance

The malignant form of astrocytoma known as glioblastoma multiforme is most commonly diagnosed primary brain tumor. This tumor is resistant to chemotherapy and radiation. There are multiple factors and pathways that are involved in the formation and progression of glioblastoma multiforme. This research project has identified a novel PKC isozyme (PKC-eta) as a molecular switch that when expressed in GBM, cells become highly proliferative and less invasive. In contrast, when this kinase is absent the GBM cells become highly invasive. Furthermore, we have identified a putative downstream target (MMP-9) of PKC-eta and a transcription factor (NF-kB) that may explain one of the many mechanisms for controlling GBM invasion both in vitro and in vivo. Understanding the functional roles of these genes in GBM invasion may provide a paradigm whereby this deadly tumor may be managed.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090851-09
Application #
8107561
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2001-04-01
Project End
2012-07-31
Budget Start
2011-08-04
Budget End
2012-07-31
Support Year
9
Fiscal Year
2011
Total Cost
$220,433
Indirect Cost
Name
University of Virginia
Department
Pathology
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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