Glioblastoma (GBM) is the most common and deadly malignant tumor of the centrail nervous system. GBM cells proliferate rapidly and diffusely infiltrate the brain, properties which render these tumors largely incurable. To effectively control GBM, the mechanisms underlying tumor cell invasion and proliferation must be understood and targeted with novei therapies. Constitutive activation of the EGFR-Ras and PI-3 kinase (PI3K) signaling pathways is a common feature in human GBM and is sufficient to cause glioblastoma-like phenotypes in mouse models. How these signaling pathways specifically control glial pathogenesis is unclear. A novel Drosophila model was created to understand the molecular basis df EGFR and PI3K driven GBM. When targeted to glia and glial precursors using genetic techniques, co-activation of EGFR and PI3K in Drosophila gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths^ mimicking the human disease. This mode! has been used to identify new regulators of glial neoplasia through genetic screens and phenotypic analyses. Human orthologs of novel genes identified in these screens were assessed for their involvement in human GBM because they represent excellent candidates for genes directly involved in the pathogenesis. My results reveal atypical kinases that are necessary forthe proliferation and survival of GBM cells, and that one of these kinases sufficient for transformation of irnmortalized astrocytes. My results suggest that overexpression of these kinases creates a feedforward loop that promotes and maintains GBM cell transformation, and disruption of this loop triggers apoptosis of GBM cells. Proposed iStudies of these kinases are aimed,at elucidating their specific roles in transformation and EGFR-PI3K signaling in both Drosophila and mammalian systems.
These studies are expected to provide key insights into glioma pathogenesis, including the identity of genes involved in tumor cell migration and invasiveness. The products of these genes may represent excellent targets for therapeutics.
|Read, Renee D; Fenton, Tim R; Gomez, German G et al. (2013) A kinome-wide RNAi screen in Drosophila Glia reveals that the RIO kinases mediate cell proliferation and survival through TORC2-Akt signaling in glioblastoma. PLoS Genet 9:e1003253|