Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

Abstract

The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.

Immune Landscape of Thyroid Cancers: New Insights

“…p53 activation is considered a final step in tumor progression. Furthermore, mutations or deletions of the PTEN (phosphatase and tensin homolog) tumor suppressor lead to the constitutive activation of the PI3K pathway and promote progression and invasion in PDTCs and ATCs ( 18 , 22 , 23 ). Moreover, a correlation between nuclear β-catenin and loss of tumor differentiation and over-expression of genes related to proliferation is known.…”

Stromal Interaction Molecule 1 (STIM1) Knock-down Attenuates Migration and Proliferation and Enhances the Expression of Thyroid Specific Proteins in Human Follicular Thyroid Cancer Cells.

“…In addition to surgery, pharmacological interventions are important in treating thyroid cancer [51]. We show that three commonly used drug, i.e., lenvatinib, paclitaxel and doxorubicin, e ciently attenuated proliferation of the ML-1 cells.…”

Novel Therapeutics in Radioactive Iodine-Resistant Thyroid Cancer

“…These include sunitinib, pazopanib, axitinib, anlotinib, cabozantinib, donafenib, dovitinib. Others have recently reviewed the available phase I and phase II trial data extensively for these agents (4,63,64). The side effect profile seems to be similar across agents, but the cross-reactivity rate is not always predictable, so a patient may not tolerate one therapeutic, but can tolerate another.…”

“…Compared to other cancers, the mutational burden on thyroid cancer is relatively low and thus they are typically poorly immunogenic (64). However, the advent of immune checkpoint inhibitors has sparked a new interest in studying the thyroid tumor microenvironment in the hopes of identifying tumors that may be more susceptible to immunotherapy.…”

“…PDTC and ATC are likely to have a higher mutational profile and thus may be more susceptible to immunotherapy (64). In fact, PD-L1 was shown to be expressed in 28.6% of ATC patients (100) and may even have a higher expression than many other solid tumors (101,102).…”