Glioblastoma multiforme (GBM) is the most aggressive and most common malignant glioma with an average overall survival is only 14.6 months. Despite aggressive therapy consisting of surgical resection, ionizing radiation, and both concurrent and maintenance chemotherapy, the disease ultimately recurs. The exact cellular and molecular mechanisms that allow these gliomas to recur remains an area of intense research, but recent evidence suggest that gliomas have a relatively small population of stem-like cells that are resistant to irradiation and chemotherapy. We have observed primary glioma cultures take on a more stem-like and aggressive phenotype when co-cultured with temozolomide, and herein propose to evaluate these this phenomena in vivo. For this purpose, we will treat murine gliomas with either radiation and/or chemotherapy, and characterize their stem- like properties upon recurrence. I plan to develop a mouse model of recurrent GBM using a genetically engineered mouse model (GEMM) of PDGF-driven glioma generated by the RCAS-tva system. Aberrant PDGF signaling is seen in approximately 30% of human GBMs, and the murine gliomas generated with this system closely resemble both the pathology and genetic characteristics the human disease. Both primary and recurrent murine gliomas will be will be compared using a variety of assays to characterize their functional stem-like properties. Specifically, the gliomas will be compared using tumorsphere formation assays, and by examining the expression of stem-like markers with immunohistochemistry and immunofluorescence. Primary and recurrent gliomas will also be compared quantitatively by examining stem-like markers using western blot analysis and quantitative real time PCR, by performing side population analysis, and by assaying orthotopic tumor forming ability. Additionally, primary and recurrent gliomas will be compared to assess any differences in the activation of signaling pathways that are well known to convey a stem-like phenotype, such as the Notch and PI3K/AKT pathway. Together, these experiments will characterize the functional stem-like properties of recurrent gliomas, and explore the pathways that may confer this phenotype. )
8. Project Narrative Glioblastoma is both the most common and most malignant primary brain neoplasm, with an average overall survival of only 14.6 months and a 5-year survival less than 10%. This proposed research training program has the potential to impact public by providing insight into the mechanisms of glioblastoma recurrence, potentially leading to an improved understanding of how the disease is able to resist therapy. )
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