title: Pazopanib enhances paclitaxel-induced mitotic catastrophe in anaplastic thyroid cancer.
abstract: 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.
authors.affiliation: Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Crescent R
authors.initials: CR
authors.lastname: Isham
authors.forename: Ayoko R
authors.initials: AR
authors.lastname: Bossou
authors.forename: Vivian
authors.initials: V
authors.lastname: Negron
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Fisher
authors.forename: Rakesh
authors.initials: R
authors.lastname: Kumar
authors.forename: Laura
authors.initials: L
authors.lastname: Marlow
authors.forename: Wilma L
authors.initials: WL
authors.lastname: Lingle
authors.forename: Robert C
authors.initials: RC
authors.lastname: Smallridge
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Sherman
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: John A
authors.initials: JA
authors.lastname: Copland
authors.forename: Keith C
authors.initials: KC
authors.lastname: Bible
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D064096:Aurora Kinase A; D064127:Aurora Kinases; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002469:Cell Separation; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007191:Indazoles; D051379:Mice; D008819:Mice, Nude; D008938:Mitosis; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology; D011743:Pyrimidines / Q000627:therapeutic use*; D034741:RNA, Small Interfering / Q000378:metabolism; D013449:Sulfonamides / Q000627:therapeutic use*; D065646:Thyroid Carcinoma, Anaplastic; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D013997:Time Factors; D050257:Tubulin Modulators / Q000627:therapeutic use
chemical_list: D007191:Indazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D050257:Tubulin Modulators; C516667:pazopanib; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel