Abstract PO-006: Exploiting non-canonical pathways of NIS regulation to enhance radioiodide uptake and identify predictive markers of recurrence in thyroid cancer

For >75 years radioiodide (RAI) has been used to target metastases and safely and specifically destroy remaining thyroid cancer cells post-surgery. Despite this, activity of the sodium iodide symporter (NIS) – the sole conduit for cellular iodide uptake – is diminished in 25-50% of thyroid cancers, limiting adequate RAI uptake for effective therapeutic ablation. Thus, identifying targetable processes that govern NIS function is urgently needed to enhance RAI uptake and diminish recurrent thyroid cancer. Here we utilized the mutated yellow fluorescent protein (YFP) as a surrogate biosensor of intracellular iodide and screened 1200 drugs (95% FDA approved), allowing us to identify putative candidate drugs which increased iodide uptake. Categorization revealed a high proportion of drugs that modulate the proteostasis network (20/50 top candidate drugs; 40%), including key processes in protein homeostasis such as endoplasmic reticulum-associated protein degradation (ERAD) and autophagy. Secondary screening validated the activity of proteostasis modulators in enhancing iodide uptake after ranking 73 compounds based on their pharmacologic properties (AUC, EC50) and specificity of response (NIS+ve vs NIS-ve YFP-thyroid cells) at ten different drug doses (0.1-50 uM). Dose-dependent increases in 125I uptake were apparent across multiple cancer cell models, as well as human primary thyrocytes, implying that proteostatic and related pathways are central to the innate control of NIS function. Subsequent mechanistic insight allowed us to evolve entirely novel combinatorial drug strategies, routinely leading to robust and significant > 5-fold increases in RAI uptake (all p Citation Format: Martin L. Read, Katie Brookes, Caitlin E.M. Thornton, Hannah R. Nieto, Alice Fletcher, Patricia Borges de Souza, Mohammed Alshahrani, Ling Zha, Jamie R.M. Webster, Luke J. Alderwick, Kristien Boelaert, Vicki E. Smith, Christopher J. McCabe. Exploiting non-canonical pathways of NIS regulation to enhance radioiodide uptake and identify predictive markers of recurrence in thyroid cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-006.