Targeting the interactome of the sodium iodide symporter to increase radioiodide uptake in differentiated thyroid cancer

Currently, the treatment of differentiated thyroid cancer combines surgical resection of the tumour and thyroid with post-surgical radioiodide therapy to ablate remaining cancer cells. Patients may be refractory to radioiodide treatment due to dysregulated expression of the Na\(^+\)/I\(^-\) symporter (NIS) or its transport to the plasma membrane of thyroid cancer cells. Although some studies have achieved increased expression of NIS, mislocalisation of the protein inside the cell remains common in thyroid tumours. This has led to recent studies exploring the post-translational processing of NIS, which have revealed therapeutic opportunities for targeting NIS-interacting proteins to modulate radioiodide uptake. This thesis appraised the established NIS interactor valosin-containing protein (VCP), as well as two new binding partners – moesin and annexin A1. Novel strategies for targeting VCP using the inhibitors CB-5083 and CB-5339 resulted in an increase in radioiodide uptake across multiple cellular models. Clotrimazole, which has previously been used as a VCP inhibitor but has limited in vivo utility due to its low bioavailability, was chemically modified. Structural analogues of clotrimazole demonstrated moderately improved effects on iodide uptake and improved bioavailability compared to the parent compound. The putative NIS interactors moesin and annexin A1 were shown to bind NIS via NanoBiT technology and to modulate its iodide uptake function, providing two entirely novel potential therapeutic targets in radioiodide refractory differentiated thyroid cancer