Abstract
Thyroid cancer is a frequently encountered endocrine malignancy. Despite the favorable prognosis of this disease, 15–20% of differentiated thyroid cancer (DTC) cases and most anaplastic types, remain resistant to standard treatment options, including radioactive iodine (RAI). In addition, around 30% of medullary thyroid cancer (MTC) cases show resistance after surgery. The evolving understanding of disease-specific molecular therapeutic targets has led to the approval of two targeted therapies (Sorafenib and Lenvatinib) for RAI refractory DTC and another two drugs (Vandetanib and Cabozantinib) for MTC. These advanced therapies exert their effects by blocking the MAPK pathway, which has been widely correlated to different types of thyroid cancers. While these drugs remain reserved for thyroid cancer patients who failed all treatment options, their ability to improve patients’ overall survival remain hindered by their low efficacy and other molecular factors. Among these factors is the tumor’s ability to activate parallel proliferative signaling pathways other than the cascades blocked by these drugs, along with overexpression of some tyrosine kinase receptors (TKR). These facts urge the search for novel different treatment strategies for advanced thyroid cases beyond these drugs. Furthermore, the growing knowledge of the dynamic immune system interaction with tumor microenvironment has revolutionized the cancer immune therapy field. In this review, we aim to discuss the molecular escape mechanisms of thyroid tumors from these drugs. We also highlight novel therapeutic options targeting other pathways than MAPK, including PI3K pathway, ALK translocations and HER2/3 receptors and their clinical impact. We also aim to discuss the usage of targeted therapy in restoring thyroid tumor sensitivity to RAI, and finally turn to extensively discuss the role of immunotherapy as a potential alternative treatment option for advanced thyroid diseases.
Highlights
For the past several decades thyroid cancer has been the most common endocrine tumor, with a ~ 5% increase in incidence each year in the USA [1, 2]
Most of these are categorized on histologic grounds as being papillary thyroid cancers (PTC), or less commonly as follicular thyroid cancers (FTC), the latter being associated with a worse prognosis
A small fraction (< 10%) of differentiated thyroid cancer (DTC) as well as many medullary thyroid cancer (MTC) and almost all anaplastic thyroid cancers (ATC) are not cured by standard therapy, instead spreading to distant metastatic sites
Summary
For the past several decades thyroid cancer has been the most common endocrine tumor, with a ~ 5% increase in incidence each year in the USA [1, 2]. The vast majority of thyroid cancers arise from thyroid follicular cells (93%) and are well-differentiated (DTC). Differentiated forms with even more aggressive clinical behavior are relatively uncommon and the highly fatal anaplastic thyroid cancers (ATC) are rare [3, 4]. The standard therapeutic approach to all thyroid cancers includes surgery, with radioactive iodine (RAI) being offered to some patients with follicular cell-derived thyroid cancers [6,7,8]. If grouped together as “advanced thyroid cancers,” patients with these aggressive forms have a less than 50% 5 year survival rate in contrast to the ~ 98% 5-year survival for iodine-sensitive DTC patients [9]
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