Tyrosine kinase inhibitors in thyroid cancer
Although the role of radioiodine (RaI) in recurrent or metastatic thyroid cancer is beyond dispute, the efficacy of this therapy is hampered by the decreased expression of the sodium iodide symporter (NIS) in DTC during the process of dedifferentiation. At present, there are no effective therapies available for RaI non-avid DTC. Conventional chemotherapy is hardly effective in DTC, and no longer recommended in international guidelines. In DTC, many genetic alterations have been identified, involving tyrosine kinase signaling pathways. In nearly all cases of PTC, genetic defects involving the RET, RAS, RAF protein kinase signaling cascade are identified. The BRAFV600E mutation has been found in 2969% of PTC and has been associated with aggressive features including extrathyroidal extension and advanced stage. Translocations of RET observed in PTC result in a chimeric protein consisting of an activated RET tyrosine kinase domain. Follicular thyroid carcinomas (FTC) frequently harbor mutations in one of the three RAS genes. The RETRASRAF pathway is interconnected with the EFGR activated cascade that among others leads to VEGF and VEGFR synthesis. Therefore, compounds targeting the activated RETRASRAF pathway and beyond may be effective in non-RaI avid DTC. The anti EGFR compound gefitinib was not successful in 27 patients with DTC, medullary or anaplastic thyroid carcinoma. In a phase II study in 60 thyroid carcinoma patients with various histologies, the VEGFR inhibitor axitinib showed a partial response of 30% (median PFS 18 months). Recently, phase II studies have been published, using multi-kinase inhibitors, including motesanib and sorafenib. Especially promising results have been reported for Sorafenib (BAY 43-9006), which is an inhibitor of RET, CRAF, wild-type and mutant (V600E) BRAF, VEGFR1, -2, -3, Flt3 and c-KIT, although no complete remissions are reported. Questions to be addressed are the relationship between genetic profile and therapy response, selection of patients for particular drugs, the combination of treatment strategies rather than using monotherapy, the response of bone metastases and the reinduction of RaI uptake and the organization of multinational clinical trials.