Abstract
The treatment options for Glioblastoma (GBM) are currently limited to resection and chemotherapy approaches, but resistance to chemotherapy is common in patients. There is an urgent need for further understanding of the underlying biology of tumorigenesis in order to develop new treatment options. Previous genomic work on GBMs has shown that the epidermal growth factor receptor (EGFR) is frequently amplified and constitutively active in GBM tumors. To discover new factors that contribute to progression of EGFR-driven GBMs, we used our Drosophila GBM model in which GBM-like glial neoplasia can be induced by glial-specific overexpression of constitutively active forms of EGFR and dp110, a subunit of Phosphoinositide 3-kinase (PI3K), using the UAS-GAL4 gene expression system. Using our Drosophila GBM model system, we performed a modifier screen in which we searched for genes and pathways that worsened or ‘enhanced’ glial neoplasia when specifically overexpressed or activated in neoplastic glia. From our screen, we identified the Toll pathway, which in Drosophila activates an NF-κB signaling pathway. Furthermore, the Toll pathway normally functions in innate immune and injury responses as well as in development and cell proliferation. Using our Drosophila GBM model, we are studying how the Toll signaling pathway and its effectors, including NF-κB, contribute to enhanced growth of neoplastic glial cells. Furthermore, using well-defined mouse genetic models and human patient-derived GBM models, we are examining whether Toll pathway regulatory and signaling mechanisms that we have uncovered in Drosophila function in EGFR-mutant GBM tumor stem cells to promote GBM progression and chemotherapy resistance.