Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies

Abstract

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.

Novel Targeted Therapies for Metastatic Thyroid Cancer—A Comprehensive Review

“…The presence of BRAF V600E mutation has been strongly correlated to the loss of NIS expression and RAI refractoriness in PTC patients [61]. BRAF activation has been shown to repress PAX8 binding to the NIS promoter by activating TGFβ (transforming growth factor β)/Smad3 signaling [62,63]. In addition, activated BRAF can also promote NIS silencing by driving histone deacetylation of the NIS promoter [63,64].…”

What Should We Prefer in the Surgical Management of Differentiated Thyroid Carcinomas?

“…The focal point of discussions is on what extent thyroidectomy and surgical methods ranging from lobectomy to total thyroidectomy are commonly used (5,6). The belief that an extensive thyroidectomy that will not leave behind functional thyroid tissue will reduce the recurrence rates and provide convenience in postoperative follow-up and adjuvant treatment is the starting point for total thyroidectomy (7,8.9).…”

“…There is an ongoing discussion about the ideal surgical approach. While the fact to what extent thyroidectomy or with what type of thyroidectomy cure is achieved is discussed on the basis of patient selection and risk factors, it is argued that the possibility of local recurrence after total thyroidectomy will be substantially reduced, reoperative surgery will be eliminated and thus the feared complications after completion thyroidectomy can be prevented (4,5,6). In patient follow-up, it was emphasized that serum thyroglobulin measurements would become more sensitive, and in the screening for recurrence or metastatic disease, increases would be achieved in ablation success with radioactive | 131 in case of recurrence or metastatic disease (7,8,9).…”

Current and Future Role of Tyrosine Kinases Inhibition in Thyroid Cancer: From Biology to Therapy

“…Another proposed mechanism is that inhibition of mTOR promotes redifferentiation through the stimulation of thyroid transcription factor-1 (TTF1), which enhances NIS expression. Nonetheless, further studies with regard to the use of mTOR inhibitors with this purpose are required [152].…”