Cytomegalovirus Gene Expression and Strain Variability in Glioma Pathogenesis

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DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM), the most common and aggressive form of adult malignant brain cancer, kills 97% of patients within five years. No major advance in determining the etiology or improving therapy has occurred in 50 years. In 2002, we showed that human cytomegalovirus (HCMV) infection occurs in over 90% of GBMs. HCMV is the most common cause of congenital brain infection and encodes for gene products that dysregulate cell cycle, apoptosis, proliferation, immune response, angiogenesis, and cellular invasion. We demonstrated that expression of the essential HCMV IE1 gene can promote proliferation of primary GBM cells (Cobbs et. al. Can Res, 2008) and that activation of PDGFR1, a growth factor receptor implicated in gliomagenesis, is required for infection (Soroceanu et al., Nature, 2008). Our recent preliminary data indicate HCMV infection preferentially occurs in the CD133+ stem-like pool of GBM cells in vivo, and induces genes that sustain the cancer stem cell phenotype. Based on this evidence, we hypothesize HCMV plays a role in initiation and promotion of GBM pathogenesis. We will focus on three essential questions to test our hypothesis: 1) Which HCMV genes are expressed in vivo in GBM and do they promote glioma pathogenesis?, 2) Does HCMV infection induce tumor formation or promote the glioma phenotype in uninfected cells of glial lineage?, and 3) Do "oncogenic" HCMV strains occur in vivo in GBM cells? We will utilize our tumor tissue bank, our extensive in vitro and in vivo brain tumor expertise, and the expertise of collaborators at OHSU and UAB for viral gene array and viral characterization experiments to answer these questions. If we demonstrate that HCMV infection plays a role in the etiology and/or progression of malignant glioma, this paradigm shift in our understanding of this disease will lead to novel therapeutic or even preventive agents for GBM.