Molecular basis and targeted therapy in thyroid cancer: Progress and opportunities

by Selleckchem | Aug 21 2023

Thyroid cancer (TC) is the most prevalent endocrine malignant tumor. Surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy are the standard TC treatment modalities. However, recurrence or tumor metastasis remains the main challenge in the management of anaplastic thyroid cancer (ATC) and radioiodine (RAI) radioactive iodine-refractory differentiated thyroid cancer (RR-DTC). Several multi-tyrosine kinase inhibitors (MKIs), or immune checkpoint inhibitors in combination with MKIs, have emerged as novel therapies for controlling the progression of DTC, medullary thyroid cancer (MTC), and ATC. Here, we discuss and summarize the molecular basis of TC, review molecularly targeted therapeutic drugs in clinical research, and explore potentially novel molecular therapeutic targets. We focused on the evaluation of current and recently emerging tyrosine kinase inhibitors approved for systemic therapy for TC, including lenvatinib, sorafenib and cabozantinib in DTC, vandetanib, cabozantinib, and RET-specific inhibitor (selpercatinib and pralsetinib) in MTC, combination dabrafenib with trametinib in ATC. In addition, we also discuss promising treatments that are in clinical trials and may be incorporated into clinical practice in the future, briefly describe the resistance mechanisms of targeted therapies, emphasizing that personalized medicine is critical to the design of second-line therapies.

Comments:

Thyroid cancer (TC) is a common type of malignant tumor affecting the endocrine system. The standard treatment options for TC include surgery, chemotherapy, radiotherapy, and radioactive iodine (RAI) therapy. However, the management of aggressive forms of thyroid cancer, such as anaplastic thyroid cancer (ATC) and radioiodine-refractory differentiated thyroid cancer (RR-DTC), remains a significant challenge due to recurrence and metastasis.

In recent years, several novel therapeutic approaches have emerged as potential options for controlling the progression of thyroid cancer. Multi-tyrosine kinase inhibitors (MKIs) and immune checkpoint inhibitors, either alone or in combination with MKIs, have shown promise in clinical research. These therapies target specific molecules and pathways involved in the growth and spread of thyroid cancer cells.

In differentiated thyroid cancer (DTC), which includes papillary and follicular thyroid cancer, the MKIs lenvatinib, sorafenib, and cabozantinib have been approved for systemic therapy. These drugs inhibit multiple tyrosine kinases, including vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which play crucial roles in tumor angiogenesis and cell proliferation.

For medullary thyroid cancer (MTC), MKIs such as vandetanib, cabozantinib, and RET-specific inhibitors (selpercatinib and pralsetinib) have shown effectiveness. These drugs target specific genetic alterations in the rearranged during transfection (RET) gene, which is frequently mutated in MTC.

In the case of anaplastic thyroid cancer (ATC), a highly aggressive and difficult-to-treat form of thyroid cancer, the combination of dabrafenib (targeting BRAF) and trametinib (targeting MEK) has shown promising results in clinical trials. This combination therapy aims to inhibit the mitogen-activated protein kinase (MAPK) signaling pathway, which is commonly dysregulated in ATC.

Several other targeted therapies are currently being investigated in clinical trials for different types of thyroid cancer. These include novel MKIs, immune checkpoint inhibitors, and therapies targeting specific genetic alterations or signaling pathways.

Despite the advancements in targeted therapies, resistance mechanisms can limit their long-term effectiveness. Understanding these mechanisms is crucial for designing second-line therapies and developing personalized treatment approaches for patients with resistant tumors.

In summary, the field of thyroid cancer treatment has seen significant progress in recent years with the emergence of targeted therapies. MKIs and immune checkpoint inhibitors, either alone or in combination, have shown promise in controlling the progression of thyroid cancer. Ongoing clinical trials and research efforts aim to identify new therapeutic targets and improve outcomes for patients with thyroid cancer.