The histology and clinical behavior of thyroid cancer are highly diverse. Although most are indolent tumors with a very favorable outcome with the current standard of care therapy, a small subset of tumors may be among the most lethal malignancies known to man. While surgery and radioactive iodine are the standard of care for differentiated thyroid cancers (DTC) and are effective in curing a majority of such patients, those with iodine-resistant cancers pose a great challenge for clinicians, as these patients have limited treatment options and poor prognoses. Medullary thyroid carcinoma (MTC) has no effective systemic therapy despite the genetic and signaling defects that have been well characterized for the last two decades. Anaplastic thyroid cancer (ATC) is one of the most aggressive solid tumors that remains fatal despite conventional multimodality therapy. Increased understanding of the pathogenesis of papillary thyroid carcinoma, the most common type of DTC, as well as ATC, has led to the development of targeted therapies aimed at signaling pathways and angiogenesis that are critical to the development and/or progression of such tumors. Development of tyrosine kinase inhibitors targeting known pathogenetic defects in MTC has led to testing of such agents in the clinic. Numerous clinical trials have been conducted over the last 5 years to examine the effects of these targeted molecular therapies on the outcomes of patients with iodine-refractory DTC, MTC and ATC. Conduction of such trials in the last few years represents a major breakthrough in the field of thyroid cancer. Several trials testing targeted therapies offer promise for setting new standards for the future of patients with progressive thyroid cancer. The purpose of this paper is to outline the recent advances in understanding of the pathogenesis of thyroid cancer and to summarize the results of the clinical trials with these targeted therapies
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