Anaplastic thyroid cancer therapy: dream or reality?

Abstract

Anaplastic thyroid cancer (ATC) is a rare thyroid malignancy representing 2 % of thyroid tumors. Usually, ATC is a lethal tumor with an overall median survival time \6 months from the diagnosis. Anecdotic cases of long-term survivors have been reported mainly in subjects with intrathyroid tumors at the time of surgical treatment [1]. The ATC management is very challenging because patients usually present with both extensive local disease and progressive distant metastases. A wide range of conventional therapeutic approaches including thyroidectomy, radiotherapy, chemotherapy, or varying combinations of these modalities have been proposed over the years, but the outcome does not appear to be significantly modified by these strategies which are indeed largely ineffective. This overall failure of all known methods of treating ATC is the main reason of the continuing search for novel treatment strategies. Recently, a very interesting study on the effectiveness of a combined treatment with bortezomib, a drug specifically targeting the ubiquitin–proteasome system, and MLN8054, which specifically inhibits Aurora kinases, has been reported [2]. The authors demonstrated that this combination was able to determine an antitumoral activity in 3 ATC cell lines, especially by reducing the cell growth rate and inducing cells apoptosis. The ubiquitin–proteasome pathway is likely the most important system for the degradation of the intracellular proteins. Recently, a novel class of antitumor agents has been identified in the proteasome inhibitors which have been demonstrated to be very active against both hematological and solid tumors. Bortezomib (Velcade) has been officially approved by the Food and Drug Administration for the treatment of multiple myeloma and it is intensively studied in other human malignant tumors. The effect of bortezomib has been evaluated in a series of carcinoma cell lines and a proapoptotic activity on both medullary and ATC cells has been demonstrated [3]. Aurora kinases are proteins which are implicated in the regulation of multiple aspects of chromosome segregation during the mitotic phase of the cell cycle. They are overexpressed in many human thyroid tissues and their degradation at the end of the mitosis is determined by the ubiquitin–proteasome pathway. Previous studies showed that MLN8054 alone, as well as other Aurora kinase inhibitors, such as VX-680 [4] or AZD1152 [5], had proapoptotic and antiproliferative effects in ATC cell lines. These findings strongly suggest the possibility that Aurora kinase inhibitors could be used in the treatment of ATC, and, likely, in other thyroid cancer not responsive to conventional therapies. The innovative aspect of the paper of Hoffmann and co-authors [2] recently published on this journal, is the demonstration of a synergistic effect of the combination of these two drugs which are directed against two different targets both very important for the inhibition of the cell cycle progression. The greatest interest of this study is the putative therapeutic role and clinical application. Several other studies have been previously published with the aim to find innovative therapeutic strategies for the treatment of ATC patients. Recently, it has been reported that the antitumor and antivascular activity of CLM94, a new cyclic amide drug, was very promising when tested on ATC cells [6]. Although with different mechanisms with respect to those exerted by bortezomib and MLN8054, also CLM94 determined a significant reduction of growth proliferation and a simultaneous increase of cell apoptosis. In R. Elisei (&) Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy e-mail: rossella.elisei@med.unipi.it