The Molecular Basis for Radioiodine Therapy

*Gerardo Hernán Carro and Juan Pablo Nicola*

### **Abstract**

Radioactive iodine (radioiodine) therapy is a standard and effective therapeutic approach for high-risk differentiated thyroid carcinomas, based on the unique ability of the thyroid follicular cell to accumulate iodide through the sodium/iodide symporter (NIS). However, a recurrent limitation of radioiodine therapy is the development of radioiodine-refractory differentiated thyroid carcinomas, which are associated with a worse prognosis. Loss of radioiodine accumulation in thyroid carcinomas has been attributed to cell dedifferentiation, resulting in reduced NIS expression and NIS intracellular retention involving transcriptional and posttranscriptional or posttranslational mechanisms, respectively. Emerging therapies targeting the oncogene-activated signal pathways potentially involved in thyroid carcinogenesis have been able to recover radioiodine accumulation in radioiodine-refractory tumors, which constitutes the rationale of redifferentiation therapies. Here, we will comprehensively discuss the molecular mechanisms underlying radioiodine therapy, refractoriness to radioiodine therapy in differentiated thyroid carcinomas, and novel strategies for restoring radioiodine accumulation in radioiodine-refractory thyroid carcinomas.

**Keywords:** differentiated thyroid cancer, sodium/iodide symporter, radioiodine therapy, radioiodine-refractory thyroid cancer, redifferentiation therapy

### **1. Introduction**

The ability of the thyroid follicular cell to accumulate iodide constitutes the cornerstone for diagnostic scintigraphy and therapy for hyperfunctioning thyroid tissue, as well as for differentiated thyroid carcinoma and their metastases after thyroidectomy [1]. Radioactive iodine (radioiodine) administration used in thyroid tissue remnant ablation after thyroidectomy and adjuvant therapy in metastatic differentiated thyroid carcinomas has been possibly the most successful internal radiation therapy ever designed. In patients with high-risk differentiated thyroid carcinomas, retrospective studies have demonstrated that the ability of tumor cells to accumulate radioiodine is the best indicator of disease-free and of overall survival [2].

Currently, thyroid hormone withdrawal and recombinant thyrotropin-stimulated radioiodine adjuvant therapy are considered in intermediate-risk carcinomas and are routinely recommended for high-risk differentiated thyroid carcinomas after total thyroidectomy [3]. However, differentiated thyroid tumors often exhibit reduced

(or even undetectable) radioiodine accumulation, compared with normal thyroid tissue, and are diagnosed as cold nodules using thyroid scintigraphy. Despite this reduction, over 70% of differentiated thyroid carcinomas accumulate radioiodine to some extent, which is still sufficient to achieve adequate radioiodine accumulation for treatment. Unfortunately, 30% of metastatic differentiated thyroid tumors completely lose their ability to accumulate iodide, with this percentage increasing up to 70% when the oncogene BRAFV600E is present. This causes thyroid tumors to become refractory to radioiodine therapy and is associated with a poor outcome. Patients with thyroid cancer metastases that accumulate iodide show a survival rate at 10 years of ~60%, while survival is drastically reduced to ~10% in patients with radioiodine refractory metastases [4]. Therefore, a better understanding of the biological mechanisms leading to differentiated thyroid carcinoma resistance to radioiodine therapy will certainly have major implications for its treatment [5].

The clinical experience of radioiodine theranostic in the management of differentiated thyroid cancer has opened up a complete new field related to developing strategies to extend this promising approach to non-thyroidal cancers. Although, in addition to thyroid cancer, functional endogenous radioiodine accumulation has only been observed in breast and ovarian cancer [6, 7], this could be key for radioiodine being used as an effective therapeutic tool. The ectopic induction of radioiodine accumulation using gene transfer has paved the way for the development of new therapeutic strategies to treat tumors with radioiodine, as in differentiated thyroid cancer. Since a pioneering study successfully induced iodide accumulation in malignant transformed thyroid cells that did not accumulate iodide, thereby rendering them sensitive to radioiodine treatment [8], a large body of evidence has shown the feasibility of inducing radioiodine accumulation in several cancer cell lines [9, 10].
