**5. Redifferentiation therapy**

Recent progress in understanding the molecular mechanisms that repress functional NIS expression has identified possibilities of new therapeutic approaches, which may expand the application of radioiodine therapy to radioiodine-refractory thyroid cancers. Indeed, some emerging therapies using MAPK signal small-molecule inhibitors, which are still in the clinical phase of study, have shown promising effects by restoring radioiodine accumulation in radioiodine-refractory differentiated thyroid cancer metastasis (redifferentiation therapy) [65].

Encouraging preclinical data, suggesting that MAPK signaling inhibition in BRAFV600E-induced thyroid cancer mouse models partially restores radioiodine accumulation [62, 64], has prompted pilot clinical studies in patients with thyroid cancer metastases resistant to radioiodide. In the first pilot clinical trial, selumetinib treatment restored iodide uptake at metastatic sites in 12 out of 20 patients with advanced radioiodine-refractory papillary thyroid cancer, and with eight of these attaining the predefined dosimetry threshold to enable radioiodine therapy with remarkable clinical responses: five of which had partial responses and with the other three having stable disease at 6 months after therapy [66]. Significantly, the therapeutic benefit of selumetinib was dependent on the mutation landscape, as all five patients carrying NRASQ61R/K, but only one of nine patients carrying BRAFV600E, redifferentiated sufficiently to be able to receive radioiodine therapy [66].

#### *The Molecular Basis for Radioiodine Therapy DOI: http://dx.doi.org/10.5772/intechopen.108073*

The BRAFV600E inhibitor dabrafenib was evaluated in patients with BRAFV600E-containing advanced radioiodine-refractory metastatic papillary thyroid cancer [67]. Dabrafenib treatment restored iodide uptake at metastatic sites in six out of 10 patients, and all these six patients were then treated with radioiodine, leading to a partial response and stable disease in two and four patients, respectively, at 3 months after therapy [67]. In a more recent pilot clinical trial, another BRAF inhibitor, vemurafenib, was evaluated in patients with BRAFV600E-containing advanced radioiodine-refractory metastatic papillary thyroid cancer [68]. Vemurafenib treatment restored or increased radioiodine accumulation in at least one metastatic lesion in six out of 10 patients. Of these, four patients attained the predefined dosimetry threshold and received radioiodide therapy, resulting in disease-free progression, with two confirmed partial responses and two with stable disease at 6 months after therapy [68]. Significantly, a transcriptomic analysis of tumor biopsy revealed that vemurafenib treatment reduced the MAPK pathway transcriptional output and induced thyroid differentiation markers [68].

In an interesting retrospective review of clinical data, six patients with radioiodinerefractory thyroid carcinomas received mutation-guided redifferentiation therapy [69]. Patients with NRASQ61K/R-harboring tumors were treated with the MEK inhibitor trametinib, and those with BRAFV600E received a combination of BRAF and MAPK inhibitors (dabrafenib and trametinib, or vemurafenib and cobimetinib). Redifferentiation therapy restored radioiodine accumulation in one of the three patients with NRASQ61K, and in all three patients with BRAFV600E. Radioiodine therapy was applied to these four patients, with three achieving a partial response and one having a stable disease under a median follow-up of 16.6 months [69]. Significantly, this study suggests that the mutation-guided MAPK pathway combined inhibition is a promising strategy to redifferentiate BRAFV600E radioiodine-refractory thyroid carcinomas, thereby rendering them suitable for radioiodine therapy.

Very recently, the results were published of the first large-scale phase 3 clinical trial conducted to evaluate the clinical benefit of adding selumetinib to adjuvant radioiodine therapy in patients with a high-risk of persistent disease or disease recurrence following initial total thyroidectomy [70]. Of the 233 patients enrolled, 97% of the placebo group and 83% of the selumetinib group completed the treatment. The complete response rate analysis at 18 months revealed no statistically significant improvement in response to selumetinib therapy compared with placebo.

The adaptive resistance to MAPK inhibitors driven by neuregulin-dependent HER3/HER2 activation observed in BRAF-mutated thyroid cancers led to testing the strategy of combining MAPK inhibitors with EGF receptor (HER) inhibitors. Significantly, the HER kinase inhibitor lapatinib prevented MAPK rebound and overcame BRAFV600E thyroid cancer cell resistance to MAPK inhibitors [63]. Similarly, in BRAFV600E expressing human thyroid cancer cell lines, the combination of lapatinib with dabrafenib or selumetinib increased radioiodine accumulation [71]. Based on the abovementioned preclinical data, a recent small pilot clinical trial assessed vemurafenib in combination with ErbB3 targeting of monoclonal antibody CDX-3379 in radioiodine-refractory metastatic thyroid cancer carrying BRAFV600E [72]. This combined therapy increased radioiodine accumulation in five out of six patients, of which four patients had a sufficient reaction to warrant radioiodine therapy. At 6 months post-therapy, two of these patients achieved a confirmed partial response [72].

Recently, Saqsena et al. [73] investigated the impact of the SWItch/Sucrose Non-Fermentable (SWI/SNF) chromatin remodeling complex on BRAFV600Edriven thyroid cancer differentiation. Mechanistically, the functional loss of different SWI/SNF subunits reduced the expression of thyroid differentiation markers by repressing chromatin accessibility to the gene encoding different transcription factors required for expression of genes regulating iodide transport and metabolism. Importantly, SWI/SNF loss promoted resistance to MAPK inhibitor–based redifferentiation therapies, reducing the effectiveness of radioiodine treatment [73]. Moreover, the preclinical data suggest that mutations affecting individual SWI/SNF complex subunits should be investigated as potential markers of resistance to redifferentiation strategies, as patients with radioiodine-refractory tumors carrying biallelic mutations in the SWI/SNF complex genes ARID1A, ARID2, or SMARCB1 failed to show a clinically significant restoration of radioiodine incorporation in response to MAPK pathway inhibition [72, 73].

The development of well-tolerated systemic therapies that selectively target oncogenic chromosomal rearrangements involved in thyroid carcinogenesis has extended the landscape of therapeutic opportunities in radioiodine-refractory thyroid carcinomas [46, 47]. Recently, different clinical case reports have revealed that the selective NTRK inhibitor larotrectinib restored radioiodine accumulation in radioiodinerefractory lung metastases harboring the NTRK fusions EML4-NTRK3, TPR-NTRK1, ETV6-NTRK3, and TPM3-NTRK1 [74–76]. Likewise, the selective RET inhibitor selpercantinib restored radioiodine accumulation in radioiodine-refractory lung metastases harboring RET fusions CCDC6-RET and NCOA4-RET [75, 77]. Moreover, a recent report presented the case of a pediatric patient with a TPM3-NTRK1 fusionpositive lung metastatic papillary thyroid carcinoma, who received redifferentiation therapy with larotrectinib as a neoadjuvant systemic approach, before the initial dose of radioiodine [78].

## **6. Conclusions**

Radioiodine accumulation in the thyroid tissue has been exploited in clinical medicine in the diagnosis and treatment of thyroid pathologies for several decades, even before the molecular characterization of the mechanism mediating iodide accumulation. Since the cloning of NIS, significant progress has been made in understanding the mechanisms mediating the resistance to radioiodine therapy, with the efficacy of the therapy having been shown to be directly related to the therapeutic dose of radiation delivered to tumor cells [79]. From a therapeutic perspective, improving radioiodine therapy for thyroid cancer is a priority for developing strategies aimed not only at enhancing radioiodine accumulation but also for promoting efficient radioiodine organification for its retention inside thyroid tumor cells, in order to improve radiation dose delivery to provide better treatment efficacy. Significantly, experimental models have revealed that phosphoinositide 3-kinase (PI3K) inhibitors seem to prolong radioiodine retention in thyroid cells [80].

The understanding of the molecular events involved in the biology of thyroid cancer has rapidly expanded the therapeutic landscape for the treatment of iodinerefractory thyroid cancer. Redifferentiation therapy has emerged as an attractive alternative in the clinical management of radioiodine-refractory thyroid carcinomas, but the promising clinical data are still preliminary. However, monotherapy with MAPK inhibitors only increases iodide accumulation in a marginal fraction of patients with metastatic thyroid cancers expressing BRAFV600E, probably due to incomplete MAPK signaling inhibition, thus suggesting that profound inhibition of MAPK signaling is required for treating these tumors effectively. The identification

*The Molecular Basis for Radioiodine Therapy DOI: http://dx.doi.org/10.5772/intechopen.108073*

of novel small-molecule inhibitors exhibiting a stronger and sustained inhibition of MAPK signaling may provide novel alternatives for maximizing the response to radioiodine therapy.

An emerging topic is the value of genetic marker-based precision management of radioiodine therapy in thyroid cancer. The co-occurrence of TERT promoter mutations in BRAFV600E-carrying recurrent papillary thyroid carcinomas is associated with loss of radioiodine accumulation. Moreover, the functional loss of SWI/SNF subunits may mediate resistance to redifferentiation therapies and might serve as biomarkers for identifying patients who will not benefit from this therapy. Although large clinical trials are necessary to validate this hypothesis, the presence of deleterious SWI/SNF subunit lesions may prompt physicians to consider treatments other than radioiodide.
