COMBINING TUMOUR TREATING fiELDS WITH ION CHANNEL BLOCKADE

Abstract AIMS Malignant brain cancer Glioblastoma multiforme (GBM) kills 3500 people per year in the UK with an average survival of 14 months with current treatment. Poor survival in GBM is due to tumour heterogeneity limiting treatment options. Randomised controlled studies have recently identified the clinical benefit of Optune elec- trotherapy in combination with chemotherapeutics for GBM. This project seeks to broaden our understanding of the mechanism of tumour treating fields (TTF) on ion channels and investigate pharmaceutical synergy with ion channel targeting agents to enhance TTF effects and lead to survival benefits for patients. METHODS Ion channel expression was evaluated in publicly available and in-house datasets, qPCR and IF. Electrophysiol- ogy was used to explore ion channel function in GBM cells. Examined the effect of Ion channel inhibitors and agonists in combination with TTF on proliferation and invasion of GBM cell lines. RESULTS SCNN, BK and K ion channel genes were identified from examining the expression in publicly available and in-house datasets, qPCR and IF. SCNN1D and SCN3A exhibit reduced expression in GBM which corresponded to worse survival. Whereas KCNE4 shows higher expression in GBM which corresponds to worse survival. Electrophysiology showed the importance of BK channels to GBM cells. Combination of SCNN and BK channel inhibitors with TTF results in an additive reduction in proliferation in GBM cell lines. Inhibition of SCNN and BK channels reduces the capacity of GBM cells to invade. CONCLUSION This work has demonstrated significant changes in ion channel gene expression between GBM, LGG and pa- tient derived cell lines which correlates with survival in patients. Pharmacological manipulation of SCNN and BK channels reduces invasion and when combined with TTF reduces tumour cell proliferation. These results provide insight into a potential future therapy.