title: Molecular Targeted Therapies of Aggressive Thyroid Cancer.
abstract: Differentiated thyroid carcinomas (DTCs) that arise from follicular cells account >90% of thyroid cancer (TC) [papillary thyroid cancer (PTC) 90%, follicular thyroid cancer (FTC) 10%], while medullary thyroid cancer (MTC) accounts <5%. Complete total thyroidectomy is the treatment of choice for PTC, FTC, and MTC. Radioiodine is routinely recommended in high-risk patients and considered in intermediate risk DTC patients. DTC cancer cells, during tumor progression, may lose the iodide uptake ability, becoming resistant to radioiodine, with a significant worsening of the prognosis. The lack of specific and effective drugs for aggressive and metastatic DTC and MTC leads to additional efforts toward the development of new drugs. Several genetic alterations in different molecular pathways in TC have been shown in the past few decades, associated with TC development and progression. Rearranged during transfection (RET)/PTC gene rearrangements, RET mutations, BRAF mutations, RAS mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways determinant in the development of TC. Tyrosine kinase inhibitors (TKIs) are small organic compounds inhibiting tyrosine kinases auto-phosphorylation and activation, most of them are multikinase inhibitors. TKIs act on the aforementioned molecular pathways involved in growth, angiogenesis, local, and distant spread of TC. TKIs are emerging as new therapies of aggressive TC, including DTC, MTC, and anaplastic thyroid cancer, being capable of inducing clinical responses and stabilization of disease. Vandetanib and cabozantinib have been approved for the treatment of MTC, while sorafenib and lenvatinib for DTC refractory to radioiodine. These drugs prolong median progression-free survival, but until now no significant increase has been observed on overall survival; side effects are common. New efforts are made to find new more effective and safe compounds and to personalize the therapy in each TC patient.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Silvia Martina
authors.initials: SM
authors.lastname: Ferrari
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Poupak
authors.initials: P
authors.lastname: Fallahi
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Ugo
authors.initials: U
authors.lastname: Politti
authors.affiliation: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa , Pisa , Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Materazzi
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome , Rome , Italy.
authors.forename: Enke
authors.initials: E
authors.lastname: Baldini
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome , Rome , Italy.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Ulisse
authors.affiliation: Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa , Pisa , Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Miccoli
authors.affiliation: Department of Clinical and Experimental Medicine, University of Pisa , Pisa , Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Antonelli
keywords: cabozantinib; dedifferentiated thyroid cancer; follicular thyroid cancer; lenvantinib; medullary thyroid cancer; papillary thyroid cancer; sorafenib; vandetanib