Antineoplastic Effect of Lenvatinib and Vandetanib in Primary Anaplastic Thyroid Cancer Cells Obtained From Biopsy or Fine Needle Aspiration.

Silvia Martina Ferrari,Alessandro Antonelli,Gabriele Materazzi,Giusy Elia,Armando Patrizio,Poupak Fallahi,Salvatore Ulisse,Concettina La Motta,Ilaria Ruffilli,Luca Quattrini,Francesca Ragusa,Sabrina Rosaria Paparo,Enke Baldini,Simona Piaggi

doi:10.3389/fendo.2018.00764

Silvia Martina Ferrari, Alessandro Antonelli + Show 12 more

Open Access

https://doi.org/10.3389/fendo.2018.00764

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Abstract

Anaplastic thyroid carcinoma (ATC) is a malignant tumor of the thyroid gland, infrequent but with a very poor prognosis, as it rapidly causes death (mean survival of about 6 months). ATC treatment includes a multimodal protocol consisting of surgery, chemotherapy (doxorubicin and cisplatin), and hyperfractionated accelerated external beam radiotherapy (median patient survival of 10 months). For this reason, the identification of an effective systemic treatment for ATC would be a major advance in the management of this deadly thyroid cancer. The opportunity to test the sensitivity to different drugs of primary cells from ATC (pATC) cultures, obtained from each patients, could improve the effectiveness of the treatment. Then, the administration of inactive therapeutics could be avoided. Our aim is to investigate the antineoplastic effect of two tyrosine kinase inhibitors (TKIs; lenvatinib, vandetanib) in pATC obtained both from biopsy (biop-pATC), and from fine needle aspiration (FNA-pATC). The antiproliferative activity of lenvatinib and vandetanib was evaluated in 6 ATC patients, on biop-pATC, such as on FNA-pATC. A significant reduction of proliferation (obtained by WST-1 assay) vs. control was shown with lenvatinib and vandetanib in FNA-pATC, as well as in biop-pATC. The percentage of apoptosis in FNA-pATC, or biop-pATC, increased with both compounds dose-dependently. pATC cells from FNA, or biopsy, had a similar sensitivity to lenvatinib and vandetanib. In conclusion, primary cells (biop-pATC or FNA-pATC) have a similar sensitivity to TKIs, and lenvatinib and vandetanib are effective in reducing cell growth, increasing apoptosis in ATC. The possibility to test the sensitivity to different TKIs in each patient could open the way to personalized treatments, avoiding the administration of ineffective, and potentially dangerous, drugs.

Highlights

Viability and Proliferation Assay In fineneedle aspiration (FNA)-primary cells from ATC (pATC) cells, a significant reduction of proliferation was observed with lenvatinib at 1 h and at 2 h, as confirmed by cell counting, too
Lenvatinib, and vandetanib are able to exert an antineoplastic action in thyroid cancer (TC), and Anaplastic thyroid carcinoma (ATC)
With this study we contribute to understand the lenvatinib, and vandetanib anticancer activity, in ATC, : [1] to the best of our knowledge, this is the first study showing the possibility to screen the antineoplastic activity of lenvatinib, and vandetanib in vitro in primary neoplastic cells obtained from cytological samples of FNA; [2] primary cells from FNA showed a chemosensitivity to tyrosine kinase inhibitors (TKIs) considerably similar to the one in primary cells from biopsy

Summary

Introduction

Anaplastic thyroid carcinoma (ATC) is a malignant tumor of the thyroid gland, infrequent but with a very poor prognosis, as it rapidly causes death (mean survival of about 6 months) [1,2,3,4].Anaplastic thyroid carcinoma treatment includes a multimodal protocol consisting of surgery [5], chemotherapy (doxorubicin and cisplatin), and hyperfractionated accelerated external beam radiotherapy [6] (median patient survival of 10 months) [6].For these reasons, it could be useful to identificate an effective systemic treatment for ATC, to ameliorate the management of this deadly thyroid cancer (TC) [7].Aurora kinase inhibitors and tyrosine kinase inhibitors (TKIs) [8], as imatinib [9] or sorafenib [10], are promising future treatments, while other studies [11,12,13,14,15] have evaluated antiangiogenic agents, like PTK787/ZK222584, aplidin, combretastatin A4 phosphate, and human vascular endothelial growth factor (VEGF) monoclonal antibodies (bevacizumab, cetuximab).small-molecule adenosine triphosphate (ATP) competitive inhibitors directed intracellularly at epidermal growth factor receptor (EGFR)’s tyrosine kinase (such as erlotinib, or gefitinib) [16, 17] are under evaluation.The antitumor activity of CLM94 [a new cyclic amide, with antiangiogenic effect and anti-VEGF receptor (R)-2], has been shown in vitro and in vivo in primary (p)ATC cells [18], such as a potent antitumor activity of the new “pyrazolo[3,4-d]pyrimidine” compounds (CLM29 and CLM24), with an antiangiogenic action and able to inhibit EGFR, the RET tyrosine kinase, VEGFR, in 8305C and pATC cells [19]. Anaplastic thyroid carcinoma treatment includes a multimodal protocol consisting of surgery [5], chemotherapy (doxorubicin and cisplatin), and hyperfractionated accelerated external beam radiotherapy [6] (median patient survival of 10 months) [6]. For these reasons, it could be useful to identificate an effective systemic treatment for ATC, to ameliorate the management of this deadly thyroid cancer (TC) [7]. Small-molecule adenosine triphosphate (ATP) competitive inhibitors directed intracellularly at epidermal growth factor receptor (EGFR)’s tyrosine kinase (such as erlotinib, or gefitinib) [16, 17] are under evaluation.

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