title: Aurora-A inhibition offers a novel therapy effective against intracranial glioblastoma.
abstract: Glioblastoma remains a devastating disease for which novel therapies are urgently needed. Here, we report that the Aurora-A kinase inhibitor alisertib exhibits potent efficacy against glioblastoma neurosphere tumor stem-like cells in vitro and in vivo. Many glioblastoma neurosphere cells treated with alisertib for short periods undergo apoptosis, although some regain proliferative activity upon drug removal. Extended treatment, however, results in complete and irreversible loss of tumor cell proliferation. Moreover, alisertib caused glioblastoma neurosphere cells to partially differentiate and enter senescence. These effects were also observed in glioma cells treated with the Aurora-A inhibitor TC-A2317 or anti-Aurora-A siRNA. Furthermore, alisertib extended median survival of mice bearing intracranial human glioblastoma neurosphere tumor xenografts. Alisertib exerted similar effects on glioblastoma neurosphere cells in vivo and resulted in markedly reduced activated phosphoThr288Aurora-A and increased abnormal mitoses and cellular ploidy, consistent with on-target activity. Our results offer preclinical proof-of-concept for alisertib as a new therapeutic for glioma treatment.
authors.affiliation: Department of Pathology, The Ohio State University, Columbus Ohio.
authors.forename: James R
authors.initials: JR
authors.lastname: Van Brocklyn
authors.affiliation: Department of Neurosurgery, The Ohio State University, Columbus Ohio.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wojton
authors.affiliation: Department of Neurosurgery, The Ohio State University, Columbus Ohio.
authors.forename: Walter H
authors.initials: WH
authors.lastname: Meisen
authors.affiliation: Department of Pathology, The Ohio State University, Columbus Ohio.
authors.forename: David A
authors.initials: DA
authors.lastname: Kellough
authors.affiliation: Oncology Translational Medicine, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Ecsedy
authors.affiliation: Department of Neurosurgery, The Ohio State University, Columbus Ohio. Department of Neuroscience, The Ohio State University, Columbus Ohio.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Department of Pathology, The Ohio State University, Columbus Ohio. Department of Neuroscience, The Ohio State University, Columbus Ohio. nllehman@yahoo.com.
authors.forename: Norman L
authors.initials: NL
authors.lastname: Lehman
mesh_terms: D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D064096:Aurora Kinase A
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