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

Background 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 in vivo, as well as the clinical relevance to radioiodide (RAI) treatment of patients with cancer. Methods We used 3D modelling, iterative design, reformulation, RAI uptake, RNA-Seq, cell surface biotinylation 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. Findings Copper diethyldithiocarbamate (Cu(DDC)2), a metabolite of the FDA-approved drug disulfiram, modulated NIS function in thyroid and breast cancer cells (P < 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 < 0.05). In mice, the copper-bound metabolite stimulated NIS activity in normal thyroid tissue, thyroid tumours and in breast orthotopic tumours (P < 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 >0.95; P < 0.001). Interpretation Our findings reveal a mechanistic pathway towards enhancing radionuclide uptake in vivo, with clinical relevance for RAI therapy and identifying survival indicators of recurrent disease.