Advanced RAI-refractory thyroid cancer: an update on treatment perspectives

Abstract

During the last decades the knowledge on follicular cell-derived thyroid cancer (TC) molecular biology has led to the evolution of a number of novel therapies for these tumors, mainly tyrosine kinase inhibitors (TKIs). Lenvantinib, sorafenib and recently cabozantinib have been approved for differentiated thyroid cancer (DTC), while larotrectinib and entrectinib for NTRK-fusion thyroid cancer. For radioiodine (RAI) refractory DTCs ongoing research aims to identify agents that may restore RAI avidity via redifferentiation protocols (vemurafenib or dabrafenib and trametinib) or combination treatments. These treatments are based on the tumor molecular signature. The treatment with targeted therapies has changed the therapeutic strategies and the disease prognosis, however drug resistance remains the main reason for treatment failure. Thus, the understanding not only of the molecular pathways implicated in tumorigenesis but also of the underlying tumoral escape mechanisms are of paramount significance for the development of new therapies for DTC. The present review focuses on the molecular landscape of DTC, the approved targeted therapies as well as the mechanisms of drug resistance. Furthermore, it points to the ongoing research and the future perspectives for the development of more efficient drugs for DTC.

Management of Progressive Radioiodine-Refractory Thyroid Carcinoma: Current Perspective

“…In particular, these second-generation kinase inhibitors (KIs) belong to two categories: RET inhibitors (selpercatinib and pralsetinib) and TRK inhibitors (larotrectinib and entrectinib). 4 , 35 …”

“… 104 NTRK fusions are also rare and especially found in PTC histotype; these alterations are more common in children than in adults (up to 26% vs 6% of cases). 4 , 105 …”

“…For example, their ability to concentrate RAI is reduced in case of low sodium iodide symporter (NIS) expression, which could be a consequence of the overactivation of the mitogen-activated protein kinase (MAPK) pathway, such as in case of BRAF-mutated TC. 4 Radiosensitivity can be lost especially in case of poorly differentiated histotypes, larger metastases, high 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake, and older age. 2 …”

“…For example, their ability to concentrate RAI is reduced in case of low sodium iodide symporter (NIS) expression, which could be a consequence of the overactivation of the mitogen-activated protein kinase (MAPK) pathway, such as in case of BRAF-mutated TC. 4 Radiosensitivity can be lost especially in case of poorly differentiated histotypes, larger metastases, high 18 F-fluorodeoxyglucose ( 18 F-FDG) uptake, and older age. 2 According to recent guidelines and recommendations, RAI refractoriness may be defined in the absence of RAI uptake in all or in some lesions on a RAI scan, and/or in case of progression despite RAI uptake, and/or after having reached a cumulative RAI activity of 22.2 gigabecquerel (gBq).…”

Towards an era of precise diagnosis and treatment: Role of novel molecular modification-based imaging and therapy for dedifferentiated thyroid cancer

“…Biomolecular modifications such as DNA methylation, protein phosphorylation, acetylation, ubiquitination, and glycosylation are significant epigenetic factors in thyroid cancer. The potential molecular basis for RAIR is the silencing of expression of thyroid-specific genes NIS, thyroglobulin (Tg), TSH receptor (TSHR), thyroperoxidase, transcription factors paired box gene-8 (PAX-8), and thyroid transcription factor-1, which are involved in alterations in cell surface receptors, signaling pathways, and nuclear receptors and epigenetics, respectively ( 4 , 8 ) ( Figure 1 ) . The following detailed description is based on the site of molecular modifications and the expression levels.…”