Glioblastoma multiforme, carries an exceptionally poor prognosis with median survival of approximately one year following diagnosis, in large part, due to the highly infiltrative behavior of glioma cells negating the effectiveness of current medical approaches. Microglia infiltrate most gliomas and release factors which influence tumor invasion. Our preliminary data indicate that soluble factors, released by microglia activate migration/invasion and up regulate phosphorylation of Pyk2 in human and rodent glioma cell lines. siRNA targeting Pyk2 eliminates the microglial effect on glioma cell migration. Based on these data we hypothesize that in the tumor microenvironment microglia release soluble factors which promote migration and dispersal of glioma cells to other brain regions through activation of the Pyk-2 intracellular signaling pathway in glioma cells. In the present study using cell biology approaches, we will examine the intracellular mechanisms involved in Pyk2 activation/phosphorylation in response to soluble factors released by microglia. We will also examine, in a murine model, the effectiveness of supplementing traditional chemotherapeutic glioma treatment with a Pyk2 blocker in order to eliminate the effect of microglia on glioma cell dispersal. To test our hypothesis we propose the following specific aims:
Specific Aim #1 : To test the hypothesis that microglia activate migration/invasion of glioma cells through a Pyk2 intracellular pathway.
Specific Aim #2 : To test the hypothesis that phospholipase C?1 (PLC?1) and epidermal growth factor receptor (EGFR) mediate microglial activated glioma mobility.
Specific aim #3 : To test the effectiveness of combined treatment of temozolomide (TMZ) and PF-562271 in decreasing glioma growth and dispersal as compared to the current treatment of TMZ alone. Validation of our hypothesis will provide a platform for developing therapeutic strategies aimed at prevention of glioma cell dispersal into healthy brain regions.
Successful outcomes from this study will provide a platform for modifying therapeutic strategies aimed at glioma treatment. We will investigate the mechanism of activation of Pyk2 in glioma cells in response to soluble factors released from microglia as it relates to glioma cell mobility. We will also examine the effectiveness of supplementing traditional chemotherapeutic glioma treatment with a Pyk2 blocker in order to eliminate the effect of microglia on glioma cell migration.
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