State of the Art in the Current Management and Future Directions of Targeted Therapy for Differentiated Thyroid Cancer

Abstract

Two-thirds of differentiated thyroid cancer (DTC) patients with distant metastases would be classified as radioactive iodine-refractory (RAIR-DTC), evolving into a poor outcome. Recent advances underlying DTC molecular mechanisms have shifted the therapy focus from the standard approach to targeting specific genetic dysregulations. Lenvatinib and sorafenib are first-line, multitargeted tyrosine kinase inhibitors (TKIs) approved to treat advanced, progressive RAIR-DTC. However, other anti-angiogenic drugs, including single targeted TKIs, are currently being evaluated as alternative or salvage therapy after the failure of first-line TKIs. Combinatorial therapy of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling cascade inhibitors has become a highly advocated strategy to improve the low efficiency of the single agent treatment. Recent studies pointed out targetable alternative pathways to overcome the resistance to MAPK and PI3K pathways’ inhibitors. Because radioiodine resistance originates in DTC loss of differentiation, redifferentiation therapies are currently being explored for efficacy. The present review will summarize the conventional management of DTC, the first-line and alternative TKIs in RAIR-DTC, and the approaches that seek to overcome the resistance to MAPK and PI3K pathways’ inhibitors. We also aim to emphasize the latest achievements in the research of redifferentiation therapy, immunotherapy, and agents targeting gene rearrangements in advanced DTC.

Editorial for the Special Issue “Molecular Biology in Targeted Radionuclide Therapy Radiopharmaceutical Design”

“…Tyrosine kinase inhibitors (TKIs) have been demonstrated to significantly improve progression-free survival; however, several drawbacks are associated with their long-term administration. Full insight into the molecular mechanisms of RAIR-DTC can lead to the development of new drugs able to improve survival [ 1 , 2 , 3 , 4 ]. In this Special Issue, Lee and coworkers [contribution 1] used clinical and molecular data from the dataset of The Cancer Genome Atlas for Thyroid Cancer (TCGA-THCA) to explore potential pathways associated with the loss of NIS expression.…”

Advances in targeted therapy and biomarker research in thyroid cancer

“…Precision medicine techniques based on molecular profiling are gaining traction ( 98 ). Comprehensive genetic analysis aids in the identification of particular mutations in individual tumors, allowing for the development of personalized therapy based on the unique molecular landscape of each patient’s thyroid cancer ( 99 ). Despite these advances, there are still obstacles, including as dealing with treatment resistance and unwanted effects ( 99 ).…”

“…Comprehensive genetic analysis aids in the identification of particular mutations in individual tumors, allowing for the development of personalized therapy based on the unique molecular landscape of each patient’s thyroid cancer ( 99 ). Despite these advances, there are still obstacles, including as dealing with treatment resistance and unwanted effects ( 99 ). Ongoing research seeks to identify new therapeutic targets, increase therapy tolerance, and develop combination methods.…”

Multi-Omics and Management of Follicular Carcinoma of the Thyroid

“…Radioisotope-based dosimetry may also assist in the early identification of dedifferentiated metastases from FTC that are not trapping the iodine to avoid futile treatment. Problems associated with the use of I-131 during the management of FTC include side-effects like bone marrow suppression, xerostomia, infertility, severe hypothyroidism during the suspension of thyroxine replacement, and the development of a second primary malignant tumor [ 127 , 134 , 137 , 138 ]. The additional concerns of the use of I-131 for treatment in patients who have extensive lungs or brain metastases are that they may develop pulmonary fibrosis that may lead to respiratory failure or brain oedema, respectively [ 92 , 127 , 138 ].…”