Combinatorial drug strategy targeting sodium iodide symporter (NIS) activity enhances radionuclide uptake in breast and thyroid settings in vivo

Background: Radioiodide (RAI) ablation therapy is hampered by diminished NIS expression, as well as intracellular retention of NIS away from the plasma membrane, especially in aggressive NIS-expressing cancers such as thyroid and breast. Recently, we reported that Cu(DDC)2 – a copper metabolite of the FDA-approved drug disulfiram – elicited a dual effect on NIS function, markedly inducing NIS expression and RAI uptake across thyroid cancer cell lines and in human primary thyrocytes1. Here, our objective was to address the hypothesis that combining drugs with distinct modes of action on NIS function, such as Cu(DDC)2 with a histone deacetylase inhibitor (HDACi), would have a maximal effect on NIS activity in vivo.

Methods: SAHA (vorinostat) was used as a candidate HDACi. NIS function was monitored by RAI (125I) uptake assays in vitro and SPECT/CT imaging via technetium-99m pertechnetate (99mTc) uptake in a MDA-MB-231 breast cancer xenograft model.

Results: Cu(DDC)2, as well as SAHA, induced significant RAI uptake in multiple breast cancer cell types (1.8-6.0-fold; P<0.001) and in stable NIS-expressing MDA-MB-231 cells (3.6-fold; P<0.001), accompanied by increased NIS protein. Given the additive effect of Cu(DDC)2 and SAHA on NIS protein levels in thyroidal TPC1-NIS cells (~1.9-fold higher than either treatment alone), we next progressed to in vivo orthotopic models (MDA-MB-231;89±16mm3;day 26 post-inoculation). SPECT/CT imaging revealed that SAHA (100 mg/kg/day) and nano-encapsulated Cu(DDC)2 (5 mg/kg/day) robustly increased 99mTc uptake in MDA-MB-231 tumours (2.3-fold; P<0.05;OTSU threshold;n=3) and thyroid glands (1.6-fold; P<0.001) compared to controls. Biodistribution studies revealed no differences in other tissues, or any change in body weight.

Conclusions: Our study identifies a new combinatorial strategy to stimulate NIS activity in vivo, with potential clinical application for improving radionuclide-based therapies and imaging across multiple cancer settings;1Brookes K et al. Dual agonism of sodium iodide symporter function in vivo.bioRxiv 2024,02.27.582332.