Regular Call Oral Abstracts

<b> Objective</b>: Exploitation of the sodium iodide symporter (NIS) in radioiodide (RAI) ablation often fails due to diminished activity. <br/>Recently, we showed that valosin-containing protein (VCP) inhibitors markedly increase NIS function by targeting proteostasis, but poor bioavailability limits their usefulness. Here, we investigated the translatable potential of clinically trialled VCP inhibitors or VCP inhibitors based on diethyldithiocarbamate (DDC)-metal complexes to enhance NIS activity. Multiple NIS-expressing cell types were studied including breast cancer cells which frequently show NIS expression but lack detectable RAI uptake due to NIS protein remaining intracellular. Further, we addressed the hypothesis that combining drugs with distinct modes of action on NIS- i.e. VCP and histone deacetylase (HDAC) inhibitors- would have a maximal effect on radionuclide uptake in vivo.<br/><br/><b> Methods</b>: NIS function was monitored by RAI (¹²⁵I) uptake assays in vitro and technetium-99m pertechnetate (^99mTc) uptake after intravenous administration in MDA-MB-231 orthotopic NSG and wild-type BALB/c mice. SAHA (vorinostat) was used as a can didate HDACi.<br/><br/><b> Results</b>: Clinically trialled VCP inhibitors CB-5083 and CB-5339 markedly induced ¹²⁵I uptake in multiple thyroid and breast cancer cells, as well as in human primary thyrocytes (up to 4.0 fold;P&lt;0.001). Subsequently, CB-5083 (25mg/kg dose;n=3) given by oral gavage failed to induce ^99mTc thyroidal uptake in wild type BALB/c mice. In an alternative strategy, the VCP inhibitor<br/> Cu(DDC)₂, as well as the HDACi SAHA, induced RAI uptake in four parental breast and four thyroid cancer cell-types (up to 6.0 fold;P&lt;0.001), and in stable NIS-expressing MDA-MB-231 cells (3.6-fold;P&lt;0.001), accompanied by increased NIS protein. Given the additive effect of SAHA and Cu(DDC)₂, we next progressed to in vivo orthotopic models (MDA-MB-231 tumours;89–16mm³;day 26 post inoculation). SPECT/CT imaging revealed that SAHA (100mg/kg/day) and a stabilised albumin reformulation of Cu(DDC)₂ (5mg/kg/day) robustly increased ^99mTc uptake into MDA-MB-231 tumours (2.3-fold;P&lt;0.05;n=3) and thyroid glands (1.6-fold;P&lt;0.001). Biodistribution studies revealed no differences in ^99mTc uptake in other major tissues, or any change in body weight.<br/><br/>Conclusion: 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.