Recent Patents on Anti-Cancer Drug Discovery Silvia M. Ferrari a , Ilaria Ruffilli 2, a , Marco Centanni b , Camilla Virili 2, b , Gabriele Materazzi c , Magdalini Alexopoulou 3, a , Mario Miccoli 4, a , Alessandro Antonelli 5,a,* and Poupak Fallahi 6, a a Department of Clinical and Experimental Medicine, University of Pisa, Via Savi, 10, I-56126, Pisa, Italy; b Department of Medico-Surgical Sciences and Biotechnologies, "Sapienza" University of Rome, Latina, Italy; c Department of Surgi- cal, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa, Italy A R T I C L E H I S T O R Y Received: July 21, 2017 Revised: February 15, 2018 Accepted: February 19, 2018 DOI: 10.2174/1574892813666180220110729 Abstract: Background and Objective: Lenvatinib is an oral, multitargeted Tyrosine Kinase Inhibitor (TKI) of Vascular Endothelial Growth Factor Receptors (VEGFR1-VEGFR3), fibroblast growth factor receptors (FGFR1-FGFR4), Platelet-Derived Growth Factor Receptor (PDGFR), rearranged during transfection (RET), and v-kit (KIT) signaling networks implicated in tumor angiogenesis. Method: Here, we review the scientific literature about lenvatinib in the treatment of thyroid cancer. Results: In vitro studies have shown antineoplastic activity of lenvatinib in Differentiated Thyroid Can- cer (DTC), mainly because of its antiangiogenetic effects, but a slight effect on thyroid cancer cell pro- liferation has been shown. In vivo Phase II, and Phase III studies in patients with aggressive DTC not responsive to radioiodine, have shown that lenvatinib administration was associated with an amelioration in Progression-Free Sur- vival (PFS) with respect to placebo (median PFS 18.2 vs. 3.6 months). However, overall survival was not significantly changed. Lenvatinib is also effective in patients resistant to sorafenib as salvage ther- apy. Adverse effects of any grade occur in more than 40% of lenvatinib-treated patients, mainly hyperten- sion, diarrhea, asthenia or fatigue, nausea, decreased appetite, and decreased weight. Discontinuations of the therapy because of adverse effects occur in about 14% of patients. Moreover, deaths considered to be drug-related can occur. Conclusion: On the basis of the above-mentioned considerations, it is necessary to prove the effective- ness of lenvatinib in the context of associated moderate to severe toxicities requiring frequent dose re- duction and delays, and for this reason, many interesting patents have been recently applied. Keywords: Anaplastic thyroid cancer, dedifferentiated thyroid cancer, follicular thyroid cancer, lenvatinib, papillary thyroid cancer, tyrosine kinase inhibitors. 1. INTRODUCTION The most frequent endocrine malignancy is Thyroid Can- cer (TC), with more than 60,000 cases each year in the US alone. Differentiated Thyroid Cancer (DTC) accounts for more than 90% of all thyroid malignancies and its incidence has been rising continuously [1-4]. Several risk factors are associated with DTC, such as the exposure to ionizing radiations in childhood or adolescence, *Address correspondence to this author at the Immuno-Endocrine Section of Internal Medicine, Professor of Medicine, Head, Laboratory of Primary Human Cells, Department of Clinical and Experimental Medicine, University of Pisa, School of Medicine, Honorary Editor, “Drugs” (IF=5.000), Via Savi, 10, I-56126, Pisa, Italy; Tel: +39-050-992318; Fax: +39-050-993472; E-mail: alessandro.antonelli@med.unipi.it that can cause especially Papillary Thyroid Cancer (PTC) [5] as well as secondary radiations, or nuclear explosions or nu- clear accidents [6, 7]. Exposure to low doses of radiations may cause the onset of thyroid nodules and cancer, too [8, 9]. Iodine deficiency is another risk factor, associated with a higher frequency of Follicular Thyroid Cancer (FTC), while an increased frequency of PTC has been shown in iodine deficient areas, after the introduction of iodine prophylaxis [10, 11]. Hashimoto’s thyroiditis is associated with PTC and thyroid lymphoma [12-15]. PTCs and FTCs are treated with total thyroidectomy and aggressive PTCs and FTCs with successive Radioactive Iodine (RAI) remnant ablation with 131I, too [7, 16]. Basal and rTSH-stimulated thyroglobulin (Tg) determination, and neck ultrasonography are the key ele- 2212-3970/18 $100.00+.00 © 2018 Bentham Science Publishers Send Orders for Reprints to reprints@benthamscience.ae Recent Patents on Anti-Cancer Drug Discovery, 2018, 13, 201-208 201 REVIEW ARTICLE Lenvatinib in the Therapy of Aggressive Thyroid Cancer: State of the Art and New Perspectives with Patents Recently Applied