Glioblastoma tumors carry an exceptionally poor prognosis with median survival of approximately one year following diagnosis. Treatment resistance and invasive nature of glioma tumors negates the effectiveness of current medical approaches. Microglia infiltrate most gliomas and release factors which influence tumor growth and invasion. It was shown that soluble factors, released by microglia activate migration, proliferation, and resistance to applied chemotherapy in cultured glioma cell lines. Previously we demonstrated that microglia promote dispersal of glioma cells through the Pyk2 signaling pathway. Our preliminary data show that pharmacological inhibition of Pyk2/FAK in glioma cells reduce proliferation and increase cytotoxic effect of temozolomide in the presence of microglia. We hypothesize that microglia release factors to promote migration, proliferation, chemotherapy resistance, and tumor recurrence through the Pyk2/FAK pathways. The use of Pyk2/FAK blockers will reduce the microglial effect on tumor growth, dispersal, recurrence, and resistance to therapy. Combinatorial therapies utilizing Pyk2/FAK inhibitors together with chemotherapeutic compounds have the potential to provide significant treatment benefits. In the present study, we will utilize resected human glioblastoma tissues and cell biology approaches to investigate the intracellular mechanisms exploited to promote microglia-activated glioma invasiveness and proliferation. We will also examine, in a murine model, the effectiveness of supplementing traditional chemotherapeutic glioblastoma treatment with a Pyk2/FAK blocker on tumor growth and recurrence. To test our hypothesis we propose the following specific aims: Specific Aim #1: To test the hypothesis that microglia activate migration, invasion and proliferation of glioma cells through Pyk2 and FAK intracellular pathways. Specific Aim #2: To investigate combined effect of temozolomide (TMZ) and the Pyk2/FAK blocker PF- 562271 on tumor growth and animal mortality. Specific aim #3: To investigate the effectiveness of combined treatment with TMZ and PF-562271 on glioma recurrence after tumor resection. Validation of our hypothesis will provide a platform for developing therapeutic strategies aimed at elimination of the microglial component on glioma growth and recurrence and, thereby, increasing treatment efficacy.

SC1GM122691

2017-09-01

2022-08-31