| Pazopanib enhances Paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer. | |
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MedLine Citation:
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PMID: 23283368 Owner: NLM Status: In-Data-Review |
Abstract/OtherAbstract:
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Anaplastic thyroid cancer (ATC) has perhaps the worst prognosis of any cancer, with a median survival of only about 5 months regardless of stage. Pazopanib monotherapy has promising clinical activity in differentiated thyroid cancers (generally attributed to vascular endothelial growth factor receptor inhibition), yet has less effective single-agent activity in ATC. We now report that combining pazopanib with microtubule inhibitors such as paclitaxel produced heightened and synergistic antitumor effects in ATC cells and xenografts that were associated with potentiated mitotic catastrophe. We hypothesized that combined effects may reflect enhanced paclitaxel-induced cytotoxicity mediated by cell cycle regulatory kinase inhibition by pazopanib. Indeed, pazopanib potently inhibited aurora A, with pazopanib/paclitaxel synergy recapitulated by aurora A short hairpin RNA knockdown or by specific aurora A pharmacological inhibition. Pazopanib/paclitaxel synergy was reversed by aurora A knockdown. Moreover, aurora A (but not B or C) message and protein levels were significantly increased in patient ATCs, and durable benefit resulted from pilot clinical translation of pazopanib/paclitaxel therapy in a patient with metastatic ATC. Collectively, these results suggest that the pazopanib/paclitaxel combination is a promising candidate therapeutic approach in ATC and that aurora A may represent a potentially viable therapeutic molecular target in ATC. |
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Authors:
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Crescent R Isham; Ayoko R Bossou; Vivian Negron; Kelly E Fisher; Rakesh Kumar; Laura Marlow; Wilma L Lingle; Robert C Smallridge; Eric J Sherman; Vera J Suman; John A Copland; Keith C Bible |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: Science translational medicine Volume: 5 ISSN: 1946-6242 ISO Abbreviation: Sci Transl Med Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-01-03 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101505086 Medline TA: Sci Transl Med Country: United States |
Other Details:
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Languages: eng Pagination: 166ra3 Citation Subset: IM |
Affiliation:
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Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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