2.1.1. Radioiodine

Radioiodine, a widely used radioisotope, has a crucial role in the diagnosis and treatment of DTC. There are several medically useful radioisotopes of iodine (125I, 131I, and 124I, etc.). However, only 131I and 124I are commonly applied in clinical settings due to their clinically acceptable radiation half-life, diagnostic or therapeutic performance, economic cost, and safety [27]. [131I]NaI can track thyroid and TC cells with γ radiation on SPECT, and damage those cells by emitting β- radiation [28]. [131I]NaI allows ablation of thyroid remnant, adjuvant therapy of TC, and therapy of TC, which vastly improves the prognosis of patients with TC [5]. 124I is another isotope of iodine emitting positron, which can be exploited for PET imaging. [124I]NaI-PET/CT has superior spatial resolution and quantification ability over [131I]NaI-SPECT [29].

Recently, numerous reports have focused on radioiodine for improving the diagnosis performance, and efficacy of treatment [30–32]. Tg tests coupled with iodine uptake assay [32], or [124I]NaI PET/CT only [30,31], are used for 131I dosimetry. Apart from performing dosimetry before 131I treatment, much attention should be given to increase the membranous expression of NIS, induce the concentration of 131I, and improve the therapeutic efficacy of 131I treatment. For RR-DTC, PDTC, and ATC, it is essential to explore agents that could increase NIS expression and augment the migration of NIS to the cell membrane. These agents mainly include but are not limited to, retinoic acid [33], mechanistic target of rapamycin kinase (mTOR) inhibitors [34], and very recently, V-Raf murine sarcoma viral oncogene homolog B (BRAF) and mitogen-activated protein kinase kinase (MAP2K1/2, MEK1/2) inhibitors, which inhibit the extracellular signal-regulated kinase (ERK) pathway responsible for tumor progression and radioiodine uptake [35,36] (Figure 1). RR-DTCs would be stabilized, or shrinkage after treatment with kinase inhibitors, owing to the suppressed signaling pathway and enhanced 131I treatment efficacy [26,37].

Lately, estrogen-related receptor gamma (ERRγ), one of the estrogen-related receptors, has gained more traction as a potential target to enhance or enable radioiodine uptake. ERRγ, a member of NR3B nuclear receptor superfamily, is a biomarker for multiple cancers, including breast cancer and prostate cancer [38]. Previous reports have shown that the ERRγ inverse agonist GSK5182 increased NIS expression and NIS-mediated iodine uptake in Kirsten rat sarcoma viral oncogene homolog (KRAS) or BRAF mutated ATC cells in vitro [39]. In addition, another ERRγ inverse agonist, DN200434, was recently shown to

increase the uptake of radioiodine in ATC tumors, identifying ERRγ as a target to enhance 131I therapy responsiveness [40] (Figure 2). It remains to be determined if DN200434 has a re-differentiative effect in patients with either RR-DTC or ATC.

**Figure 1.** [ 124I]NaI PET/CT images of patients with RR-DTC or PDTC with or without kinase inhibitors. (**A**) PET/CT images showed enhanced iodine uptake of lesions post-treatment with selumetinib in nearly all previously negative head, lung, and sacroiliac bone metastases. Reproduced with permission from [35], copyright 2013 Massachusetts Medical Society. (**B**) PET/CT images showed enhanced radioiodine uptake of lesions in the neck and lung after treatment with vemurafenib, a specific BRAFV600E inhibitor. Reproduced with permission from [36], copyright 2019 Endocrine Society.

**Figure 2.** [ 124I]NaI-PET/CT demonstrates enhanced iodine uptake in CAL62 ATC tumor after treatment with DN200434. The arrows indicate the ATC tumor. Reproduced with permission from [40], copyright 2019 American Association for Cancer Research.
