The sodium–iodide symporter (NIS) is the sole known conduit of iodide into human cells. Researchers from the University of Birmingham have identified new combinatorial drug strategies to stimulate NIS activity. These findings have potential clinical application for improving radionuclide-based therapies and imaging across multiple cancer settings.
The first clinical use of radioiodide therapy in 1946 for thyroid cancer was a huge milestone in nuclear medicine and oncology.1 Since then, β-emitting radioiodide (131I) has become a standard treatment and is widely used to safely, efficiently and specifically destroy remaining thyroid cancer cells post-surgery and to target metastases.
Despite the effectiveness of radioiodide therapy, there is a worrying prediction that the total number of deaths due to thyroid cancer will increase over the next 25 years.2 Globally, the total mortality for thyroid cancer has been projected to rise by 91.2% by 2050, and this figure is even higher for the continents of Asia (102.4%) and Africa (169.4%).
Poor tumoural uptake of 131I is fundamental to the failure of radioiodide therapy, and is typically diminished in 25–50% of thyroid cancer patients. For example, patients with radioiodide-resistant thyroid cancer, particularly those with metastatic disease, have a life expectancy of only three to five years.3
THE NIS: A KEY DRUGGABLE TARGET
To address this clear unmet medical need, several research groups have investigated the NIS as a key druggable target to enhance radioiodide therapy.4 This is because the NIS is the sole transporter responsible for specific cellular iodide uptake at the plasma membrane, and hence critical for 131I internalisation. It is also well-recognised that any alterations in NIS activity caused by diminished NIS expression and/or mislocalisation away from the plasma membrane can lead to tumoural radioiodide refractoriness (Figure 1).
The inherent complexity of how NIS activity is dysregulated in cancer presents a major hurdle for the thyroid research community to overcome. For instance, the NIS is regulated by a plethora of mechanisms, including transcription factors, post-translational modifications, histone acetylation, DNA methylation, hormonal signalling, autophagy, oxidative stress and microRNAs/long non-coding RNAs.4 Many of these pathways are altered in thyroid tumour cells. which adds to the complexity of developing NIS-targeting therapeutic strategies.
Figure 1. NIS activity is compromised by diminished expression and mislocalisation away from the plasma membrane, which contributes to the failure of 131I as a therapeutic strategy and poor survival rates, particularly in aggressive and metastatic disease. NIS structure reproduced from the AlphaFold Protein Structure Database under CC-BY 4.0 licence. ©EMBL-EBI and DeepMind Technologies Ltd 2022. Figure created using biorender.com.
IDENTIFYING NIS TARGETABLE PATHWAYS
We recently undertook a series of drug screening studies to identify the key targetable pathways modulating NIS activity in thyroid cancer cells.5–7 One important finding was the identification of cellular processes capable of modifying radioiodide uptake outside the canonical pathways (e.g. BRAF/MEK signalling) of NIS processing.
For example, we conducted a high-throughput screening of compounds approved by the US Food and Drug Administration.6 In this study, we enhanced NIS activity and subsequent radioiodide uptake by targeting the ubiquitin–proteasome system using the anti-alcohol drug disulfiram, as well as valosin-containing protein (VCP) inhibitors, including the antihistamine carebastine and antifungal clotrimazole.6
An under-studied aspect of NIS processing in thyroid cancer cells is its trafficking to, and retention at, the plasma membrane. In earlier work, we showed that the proto-oncogene PTTG1-binding factor acts as an NIS-interacting protein capable of inducing NIS endocytosis when overexpressed in cancer cells, leading to diminished radioiodide uptake.8 More recently, we characterised AP2 subunit genes as NIS interactors, implicating the AP2 complex in clathrin-dependent endocytosis of NIS.7
Based on these observations, we were then able to successfully demonstrate that the antimalarial drug chloroquine was effective at blocking NIS endocytosis, thereby identifying a promising non-canonical approach to retain NIS at the plasma membrane and enhance radioiodide uptake.7
Figure 2. Targetable processes to enhance NIS function and radioiodide therapy. Valosin-containing protein is a critical component of ubiquitin–proteasome and autophagy–lysosome pathways. Chloroquine inhibits fusion of autophagosomes and lysosomes, endolysosomal degradation and endocytosis. Histone deacetylase inhibitors (HDACi; e.g. SAHA) promote NIS transcription. Disulfiram inhibits proteasomal degradation. ER, endoplasmic reticulum; ERAD, endoplasmic reticulum-associated degradation. Credit in footnote.
COMBINATORIAL DRUG STRATEGIES
Combinatorial drug strategies offer many advantages, including enhanced efficacy, broader targeting and synergistic effects. To date, a wide range of combinatorial drug strategies to target NIS function have been evaluated. In particular, combined targeting of MAP kinase pathways which generally drive tumourigenesis in thyroid cancer (e.g. BRAF/MEK inhibitors, such as dabrafenib and trametinib) has shown some promise clinically in overcoming radioiodine refractoriness.9 However, issues of drug resistance and adverse events with BRAF/MEK inhibitors remain, and new alternative strategies targeting NIS function are urgently needed.
Due to the complexity of NIS regulation, we recently combined drugs that target distinct cellular processes to maximise the induction of NIS activity (Figure 2). We showed, for instance, that co-treatment of thyroid cancer cells with the histone deacetylase inhibitor SAHA, to induce NIS mRNA, and VCP inhibitors (such as ebastine, astemizole or clotrimazole) led to significant increases in radioiodide uptake compared with SAHA alone.6 Similarly, combining SAHA with the endocytosis inhibitor chloroquine led to effective and additive increases in radioiodide uptake in thyroid cancer cells in vitro,6 as well as in thyroid glands of wild type BALB/c mice in vivo.7 Encouragingly, we again recently showed that combining SAHA with a metabolite of disulfiram gave robust induction of NIS function in an in vivo orthotopic model of breast cancer.10 Together, our findings indicate that new combinatorial strategies targeting NIS function might represent a feasible option to enhance radioiodide therapy.
FUTURE CONSIDERATIONS
There has been considerable progress in identifying new combinatorial drug strategies capable of inducing NIS function in thyroid cancer cells refractory to radioiodide uptake. The next significant challenge will be to thoroughly examine the biological impact of these new drug combinations on NIS activity in animal models of thyroid cancer.
Of critical importance will be to study the translatable potential of these drugs to enhance radioiodide ablation, and whether further drug refinement by rational design or reformulation is required to achieve sufficient tumour accumulation. It is envisaged that, if progress can be maintained, then better therapeutic options will become available to the clinician, in order to facilitate radioiodide ablation of thyroid cancer in the near future.
MARTIN L READ Senior Research Fellow
KATIE BROOKES PhD Student
CHRISTOPHER J McCABE Professor of Molecular Endocrinology
Department of Metabolism and Systems Science, School of Medical Sciences, College of Medicine and Health, University of Birmingham
REFERENCES
- Seidlin SM et al. 1946 Journal of the American Medical Association https://doi.org/10.1001/jama.1946.02870490016004.
2. Ferlay J et al. 2024 Global Cancer Observatory: Cancer Tomorrow version 1.1. Lyon, France: International Agency for Research on Cancer. https://gco.iarc.who.int/tomorrow/en.
3. Schlumberger M et al. 2014 Lancet Diabetes & Endocrinology https://doi.org/10.1016/s2213-8587(13)70215-8.
4. Riesco-Eizaguirre G et al. 2021 Endocrine-Related Cancer https://doi.org/10.1530/ERC-21-0217.
5. Fletcher A et al. 2020 Cancer Research https://doi.org/10.1158/0008-5472.CAN-19-1957.
6. Read ML et al. 2022 Cell Chemical Biology https://doi.org/10.1016/j.chembiol.2021.07.016.
7. Read ML et al. 2024 Clinical Cancer Research https://doi.org/10.1158/1078-0432.CCR-23-2043.
8. Smith VE et al. 2009 Journal of Cell Science https://doi.org/10.1242/jcs.045427.
9. Leboulleux S et al. 2023 Clinical Cancer Research https://doi.org/10.1158/1078-0432.ccr-23-0046.
10. Brookes K et al. 2024 SSRN https://doi.org/10.2139/ssrn.4996070
FOOTNOTE
Credit for Figure 2: NIS structure reproduced from the AlphaFold Protein Structure Database under CC-BY 4.0 licence. ©EMBL-EBI and DeepMind Technologies Ltd 2022. Figure created using biorender.com.
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