Alisertib demonstrates significant antitumor activity in bevacizumab resistant, patient derived orthotopic models of glioblastoma.
Aurora A kinase (AURKA), a member of the serine/threonine kinase family, plays a critical role in cell division, and it is widely overexpressed in a variety of tumors including glioblastoma (GBM). Alisertib (MLN8237) is an orally administered selective AURKA inhibitor with potent antiproliferative activity, currently undergoing clinical testing in different tumor types. In vitro evaluation of alisertib against the primary GBM lines, GBM6, GBM10, GBM12 and GBM39 showed significant antitumor activity with IC50sranging between 30 and 95 nM. Orthotopic xenografts of GBM10 and the bevacizumab resistant lines GBM6 and GBM39 were established by implantating 3 × 105cells in the caudate nucleus of nude mice; animals were randomized to treatment with either alisertib 30 mg/kg/day or vehicle. In all three models, treatment with alisertib resulted in a statistically significant prolongation of survival (p < 0.0001). In addition, alisertib administration in these mice decreased phosphorylated aurora-A, induced mitotic arrest and significantly decreased histone H3 phosphorylation in tumors. In conclusion, alisertib displays significant antitumor activity against primary GBM lines and xenografts, including patient derived GBM lines resistant to bevacizumab; these data support clinical translation in GBM.
Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Kurokawa
Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Geekiyanage
Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Allen
Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Iankov
Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Schroeder
Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Carlson
Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Bakken
Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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Sarkaria
Translational Medicine, Millennium Pharmaceuticals, Inc. (A Wholly Owned Subsidiary of Takeda Pharmaceutical Company Limited), Cambridge, MA, 02139, USA.
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Ecsedy
Department of Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.
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D'Assoro
Essentia Health Oncology, 420 E 1st St, Duluth, MN, 55805, USA.
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Friday
Departments of Oncology and Molecular Medicine, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. galanis.evanthia@mayo.edu.
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Galanis
D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000009:adverse effects; D064096:Aurora Kinase A / Q000378:metabolism; D001381:Azepines / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000009:adverse effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy* / Q000473:pathology; D006657:Histones / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
D000074322:Antineoplastic Agents, Immunological; D001381:Azepines; D006657:Histones; C550258:MLN 8237; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068258:Bevacizumab; D064096:Aurora Kinase A
Alisertib; Aurora A; Bevacizumab; GBM; Resistance