Division of Medical Oncology, Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
Sci Transl Med. 2013 Jan 2;5(166):166ra3. doi: 10.1126/scitranslmed.3004358.
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.
间变性甲状腺癌（ATC）的预后可能是所有癌症中最差的，中位生存期仅约 5 个月，与分期无关。帕唑帕尼单药治疗在分化型甲状腺癌中具有有前景的临床活性（通常归因于血管内皮生长因子受体抑制），但在 ATC 中的单药活性较低。我们现在报告，帕唑帕尼与微管抑制剂（如紫杉醇）联合使用可在 ATC 细胞和异种移植物中产生更高的协同抗肿瘤作用，与有丝分裂灾难增强有关。我们假设联合作用可能反映了帕唑帕尼通过抑制细胞周期调节激酶来增强紫杉醇诱导的细胞毒性。事实上，帕唑帕尼强烈抑制极光激酶 A，帕唑帕尼/紫杉醇协同作用可通过极光激酶 A 短发夹 RNA 敲低或特定极光激酶 A 药理学抑制来重现。极光激酶 A 敲低可逆转帕唑帕尼/紫杉醇协同作用。此外，患者 ATC 中的极光 A（而非 B 或 C）mRNA 和蛋白水平显著增加，并且在一名转移性 ATC 患者中进行帕唑帕尼/紫杉醇治疗的试点临床转化中获得了持久的益处。综上所述，这些结果表明，帕唑帕尼/紫杉醇联合治疗是 ATC 中一种很有前途的治疗方法，极光 A 可能是 ATC 中一种潜在可行的治疗分子靶标。
