Emerging therapeutics for advanced thyroid malignancies: rationale and targeted approaches

Abstract

Introduction Thyroid cancer is an emerging public health concern. In the U.S., its incidence has doubled in the past decade, making it the 8th most commonly diagnosed neoplasm in 2010. Despite this alarming increase, most thyroid cancer patients benefit from conventional approaches (surgery, radioiodine, radiotherapy, TSH suppression with levothyroxine) and are often cured. Nevertheless, a minority have aggressive tumors resistant to cytotoxic and other historical therapies; these patients sorely need new treatment options. Areas covered Herein the biology and molecular characteristics of the common histological types of thyroid cancer are reviewed to provide context for subsequent discussion of recent developments and emerging therapeutics for advanced thyroid cancers. Expert opinion Several kinase inhibitors, especially those targeting VEGFR and/or RET, have already demonstrated promising activity in differentiated and medullary thyroid cancers (DTC, MTC). Although of minimal benefit in DTC and MTC, cytotoxic chemotherapy with anti-microtubule agents and/or anthracyclines in combination with intensity modulated radiation therapy appears to extend survival for patients with locoregionally-confined anaplastic thyroid cancer (ATC), but to have only modest benefit in metastatic ATC. Further discovery and development of novel agents and combinations of agents will be critical to further progress in treating advanced thyroid cancers of all histotypes.

A Potential Role for Immunotherapy in Thyroid Cancer by Enhancing NY-ESO-1 Cancer Antigen Expression

“…Papillary thyroid cancer (PTC), which accounts for a majority of thyroid cancer cases, is usually curative by surgery, radioiodine treatment, and thyroidstimulating hormone suppression (2,3). Some patients with aggressive forms of PTC do poorly and there is a lack of effective therapies for these patients.…”

Personalized Therapy in Patients With Anaplastic Thyroid Cancer: Targeting Genetic and Epigenetic Alterations

“…Sorafenib, a broad spectrum kinase inhibitor (multityrosine kinase inhibitor (TKI)), including VEGFR2 inhibition, (Figure 1) was recently approved by the U.S. Food and Drug Administration (FDA) for radioiodine-resistant metastatic differentiated thyroid cancer (41). However, it did not show a significant therapeutic effect in patients with ATC, leading to additional side effects that include cardiovascular toxicity and dyspnea ( Axitinib (Figure 1), a VEGFR2 inhibitor (46), showed therapeutic efficacy only in 1 out of 2 patients with ATC (42). Pazopanib, another TKI, similarly to sorafenib also failed to significantly improve the clinical outcome of patients with ATC (42) (47).…”

“…Also, one factor that might be a reason for these TKIs to show little clinical significance in ATC is the inability to administer doses at high enough concentrations (20). Dosing of these drugs, in general, is something that needs to be worked out, as different plasma levels of administered TKIs are seen among patients who received the same doses (42). With such a complex pathogenesis, many signaling pathways lose proper regulation, giving the tumor the ability to gain drug resistance.…”

“…(42) (43). In particular, patients with PTC or FTC treated with sorafenib in phase II clinical trials showed either stable disease or partial responses(44) (45); whereas, patients with ATC showed rapid clinical progressive disease after drug administration, making it less useful for this malignancy (44)(45).…”

FOXD3 regulates anaplastic thyroid cancer progression

“…Although conventional therapeutic modalities are effective in early-stage thyroid cancer patients, they are largely ineffective in advanced stage patients with differentiated, undifferentiated/anaplastic or medullary thyroid cancers (DTC, ATC or MTC) [1–4]. Hence, there is an urgent need to discover, develop and critically evaluate novel therapeutic drugs to clinically treat thyroid cancer patients [4]. Thyroid cancers are associated with mutations in many critical genes like BRAF, RAS , catenin (cadherin-associated protein), beta 1, PIK3CA, TP53, AXIN1, PTEN , and APC [5].…”