Aurora-A (AURKA) is an exciting new drug target for the treatment of glioblastoma (GB). GB is a highly malignant, mostly adult brain tumor for which only marginal improvement in survival time has been achieved. AURKA is a serine-threonine kinase that drives mitotic progression and cytokinesis. It also positively regulates several proproliferative signaling pathways, including c-Myc, cyclin B/CDK1, NF-kB and Wnt signaling and negatively regulates p53. AURKA is oncogenic when overexpressed in cultured cells and its altered expression promotes genomic instability and malignancy. Our preliminary data show that the selective AURKA inhibitor MLN8237 potently inhibits proliferation of GB cells in vitro and extends animal survival in a GB orthotopic xenograft model. We will study the efficacy of MLN8237 against GB patient-derived neurosphere tumor stem-like cells in vitro, and in GB orthotopic xenograft mouse models using neurosphere stem-like cells from multiple patients. Alternate AURKA inhibitors and anti-AURKA RNAi will also be used to verify the efficacy of inhibiting this kinase and to distinguish off-target effects, respectively. These in vitro and animl studies will also investigate the possible synergistic effects of MLN8237 with other GB therapies, e.g., temozolomide, radiation, angiogenesis inhibitors and other chemotherapeutic drugs. We will perform experiments to determine if activated AURKA expression or candidate important interacting proteins, e.g., Bora and TPX2, predict sensitivity to MLN8237, an important step toward understanding which GB patients would likely benefit most from AURKA inhibition. We will determine the mechanisms of AURKA inhibition of tumor growth by examining effects of inhibitors on GB cell apoptosis, differentiation, senescence and genomic stability, as well as the regulation of biochemical pathways mediating these responses. Tumor hypoxia and angiogenesis are important mechanisms of tumor progression in gliomas. AURKA is induced by hypoxia and may itself increase angiogenic factors such as VEGF. We will study the effects of AURKA knockin and knockdown on important angiogenic signaling proteins, e.g., HIF-1?, GSK-3 and VEGF, in cultured cells to investigate possible direct and indirect roles of AURKA in GB angiogenesis. Since AURKA is induced by hypoxia we will test the ability of AURKA inhibitors to potentiate bevacizumab, which may potentially optimize the latter's clinical usefulness. We will also examine measurable biological effects of AURKA inhibition on angiogenesis, tumor invasion and genomic stability using in vitro and animal models.
Glioblastoma is the most common type of brain cancer in adults. It is a very malignant tumor and most patients survive only about one year after diagnosis. Aurora-A inhibitors are a new type of chemotherapy drug that have shown promise against several types of cancer. The purpose of this grant proposal is to perform laboratory testing in cell cultures and mice to confirm that one of these new drugs is an effective weapon against glioblastoma. The ultimate goal of these studies is that this drug will be used to treat glioblastoma patients and allow them to survive longer.
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