**Author details**

lines originating from different epithelial thyroid tumor histotypes, compared with normal thyrocytes, as well as in DTC and ATC tissues, compared with normal matched tissues [60, 98, 122]. In addition, a study aimed to evaluate the gene expression profile in ATC identified *AURKA* as one of the most frequently and most strongly overexpressed genes in these tumors [123]. In fact, gain of chromosome 20q, where *AURKA* is located (20q13.2), is frequently encountered in ATC [124]. Based on these findings, the potential therapeutic value of Aurora kinase inhibition on the proliferation and growth of PTC and ATC cells has been evaluated in preclinical studies [125–130]. In particular, different pan-Aurora kinase inhibitors, including the MK-0457 (VX-680), the SNS-314 mesylate, and the ZM447439 have been evaluated *in vitro* [126–129]. These molecules were found to inhibit proliferation of ATC cells in a time- and dosedependent manner and to impair cancer cell colony formation in soft agar. Cell cultures exposed to pan-Aurora inhibitors revealed an accumulation of tetra- and polyploid cells because of endoreplication events followed by the activation of caspase-3 and accumulation of a sub-G0/G1 cell population, both indicative of apoptosis [126–129]. Treated cells showed mitotic alterations consistent with the inhibition of Aurora kinases, including major impairment of centrosome functions, with abnormal spindle formation characterized by the presence of short microtubules, inhibition of histone H3 phosphorylation, and inability to complete the cytokinesis. The effects of a selective inhibition of either Aurora-A or Aurora-B have been also explored [125, 129, 131]. The selective inhibition of Aurora-B expression, by means of RNA interference, or function, by means of small-molecule compounds (e.g., AZD1152), has been reported to significantly reduce growth and tumorigenicity of ATC-derived cells, both *in vivo* and *in vitro* [125]. In the same way, functional inhibition of Aurora-A by MLN8054 in a panel of ATC-derived cell lines has been shown to block cell proliferation and to induce cell cycle arrest and apoptosis [129]. In xenograft experiments, the drug was capable of reducing tumor volume by 86% [129]. Interestingly, the combined treatment with MLN8054 and bortezomib, targeting the ubiquitin-proteasome system, showed additive effects on ATC-derived cell proliferation and apoptosis, compared with monotherapy [131]. More recently, pazopanib, a multi-target inhibitor of tyrosine kinases including the VEGFR (vascular endothelial growth factor receptor), shown to have impressive therapeutic activity in patients affected by radioactive iodine-refractory DTC, was tested in a phase II clinical trial on ATC patients [132, 133]. Despite several of them treated with pazopanib had a transient disease regression, no response evaluation criteria in solid tumors (RECIST) response was obtained [131]. Moreover, in a preclinical study on a panel of ATC-derived cell lines, pazopanib was found to potentiate the cytotoxic effects of paclitaxel *in vitro* and in xenograft experiments [134]. These pazopanib effects were attributed to an unexpected off-target inhibition of Aurora-A in ATC-derived cell lines. In fact, the same results were obtained when combining paclitaxel and MLN8237, a selective Aurora-A inhibitor. In the same study, the authors also showed that the combined administration of pazopanib and paclitaxel attained a marked and durable regression of lung

In conclusion, the preclinical and clinical data so far available indicate that Aurora kinase inhibitors may have a therapeutic potential for the treatment of the more aggressive thyroid cancers either in monotherapy or, more likely, in combination therapy with antimicrotubule

metastasis in a single ATC patient [134].

106 Anti-cancer Drugs - Nature, Synthesis and Cell

drugs.

Enke Baldini, Chiara Tuccilli, Salvatore Sorrenti, Domenico Mascagni, Stefano Arcieri, Angelo Filippini and Salvatore Ulisse\*

\*Address all correspondence to: salvatore.ulisse@uniroma1.it

Department of Surgical Sciences, "Sapienza" University of Rome, Rome, Italy
