Exploiting non-canonical pathways of NIS regulation to enhance radioiodide uptake and identify predictive markers of thyroid cancer recurrence

Research output: Contribution to journalAbstractpeer-review

Abstract

Objectives
For >75 years radioiodide has been used to target metastases 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 radioiodide uptake for effective therapeutic ablation. The objective of this study was to identify targetable processes that govern NIS function to enhance radioiodide uptake, as well as to determine predictive markers of recurrence.

Methods
Here, we utilised NIS in high-throughput drug screening (1200 drugs, 95% FDA approved), allowing us to identify putative candidate drugs which increased iodide uptake. TCGA was appraised to investigate the association of drug target genes with recurrence in radioiodide-treated thyroid cancer patients.

Results
Rigorous evaluation of leading drug candidates identified multiple proteostasis pathways, including proteasomal degradation and autophagy, that are central to the cellular processing of NIS. Utilizing inhibitors targeted to distinct cellular processes, we pinpoint combinatorial drug strategies giving robust >5-fold increases in radioiodide uptake (all p < 0.001). We also reveal significant dysregulation of core proteostasis genes in human thyroid tumours, identifying a 13-gene riskscore classifier as an independent predictor of recurrence in radioiodide-treated patients.

Conclusion
Whilst oncogene activation can suppress NIS function, our study has identified new non-canonical pathways that regulate radioiodide uptake. Collectively, we propose a new model for the targetable steps of intracellular processing of NIS, with translatable potential to address the lack of clinical options for patients treated with radioiodide who typically have poorer clinical outcomes.


Details

Original languageEnglish
JournalNuclear Medicine Communications
Volume42
Issue number5
Publication statusPublished - May 2021
EventBritish Nuclear Medicine Society Online Spring Meeting -
Duration: 18 May 202119 May 2021
https://www.bnms.org.uk/page/BNMSVirtualSpring1daymeeting2021

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