The ability of the Aurora-A inhibitor alisertib to potentiate the anti-proliferative effects of VEGFR inhibitors in glioblastoma cells
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Series/Report no.:2017 Richard J. and Martha D. Denman Undergraduate Research Forum. 22nd
Glioblastoma (WHO grade IV glioma) is the most common primary malignant brain tumor in adults, and is generally incurable. The prognosis is poor, with a median survival of only 14.6 months. Aurora-A, a serine-threonine kinase critical for a variety of cellular processes including centrosome duplication, spindle assembly, and mitotic exit, is widely overexpressed in glioblastoma. Additionally, malignant gliomas also possess high levels of vascular endothelial growth factor (VEGF), which is associated with pathological vasculogenesis and angiogenesis. Therefore, drugs that inhibit Aurora-A, in addition to VEGF and its receptor, are of interest in order to inhibit neovascularization and cellular proliferation. It was hypothesized that combining alisertib with a VEGFR inhibitor, such as cabozantinib or vandetanib, would work synergistically to inhibit glioblastoma cell proliferation and induce cell death via apoptosis. The glioblastoma cell lines U87 and U1242 were treated with a range of concentrations of alisertib and either cabozantinib or vandetanib. Glioblastoma cells were seeded at 600 cells/60-mm plate. After 72 hours of drug exposure, cell colonies were counted, and the percent survival was graphed relative to the control untreated cells. The results of these experiments were analyzed using Chou-Talalay and Bliss Independence models to test for synergism and determine their statistical significance. Preliminary results of in vitro colony formation assays suggest that alisertib works synergistically to inhibit cellular proliferation with both cabozantinib and/or vandetanib in both cell lines; further in vitro testing is currently in progress. Because of the lack of effective treatments available for glioblastoma, successful completion of this study may provide a basis for clinical trials including these drug combinations. The results of such clinical trials may expand the potential treatment options for this aggressive disease, and improve the lives of glioblastoma patients.
Health Professions - Laboratory/Cellular (The Ohio State University Denman Undergraduate Research Forum)
Academic Major: Health Sciences Program
This work was supported by the NIH grant R01-NS081125.