Disulfiram metabolite Cu(DDC)₂ enhances radionuclide uptake in vivo revealing insights into tumoural ablation resistance

<b>Background</b> Exploitation of the sodium iodide symporter (NIS) has potentially broad clinical application across different tumour ablative settings but often fails in aggressive cancer due to diminished transport activity. We aimed to discover whether enhancing NIS function by modulating proteostasis was targetable<i> in vivo</i>, as well as the clinical relevance to radioiodide (RAI) treatment of patients with cancer.<br/><br/><b>Methods</b> We used 3D modelling, iterative design, reformulation, RAI uptake, RNA-Seq, cell surface biotinylations assays and NanoBRET in transformed cell lines and primary thyroid cells from patients to identify new drugs targeted at enhancing NIS function and to uncover their respective mechanisms. Systemic drug responses were monitored via ^99mTc pertechnetate gamma counting and SPECT/CT imaging in wild-type BALB/c and Tg-rtTA/tetO-BRAFV600E mice, as well as orthotopic NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ (NSG) breast cancer.<br/><br/><b>Findings</b> In this study, we discovered that copper diethyldithiocarbamate (Cu(DDC)₂), a metabolite of the FDA-approved drug disulfiram, modulated NIS function in thyroid and breast cancer cells (p &lt; 0.05). Mechanistically, Cu(DDC)₂ elicited a dual effect on NIS function, targeting valosin containing protein (VCP) – a key regulator of proteostasis – as well as inducing potent transcriptional responses (p &lt; 0.05). In mice, the copper-bound metabolite stimulated NIS activity in normal thyroid tissue, thyroid tumours and in breast orthotopic tumours (p &lt; 0.05), the latter augmented by the histone deacetylase inhibitor vorinostat (SAHA). Notably, there was clinical association of drug-perturbed genes in RAI-treated thyroid cancer, enabling construction of a robust dual risk score classifier for predicting recurrence (AUC &gt; 0.95; p &lt; 0.001). <br/><br/><b>Interpretation</b> Our findings reveal a new mechanistic pathway towards enhancing radionuclide uptake <i>in vivo</i>, with clinical relevance for RAI therapy and identifying survival indicators of recurrent disease.<br/><br/>