HGG-28. CLIC1 and CLIC4 ion channel deficiency confers increased sensitivity to tumour treating fields and improved survival in paediatric glioblastoma

Abstract

Paediatric Glioblastoma Multiforme (pGBM) is a lethal brain cancer with an average survival of 14 months. Due to the scarcity of effective treatment, pGBM forms the leading cause of CNS cancer death in children. Optune™ is a non-invasive therapy that uses alternating electric fields – coined TT fields - to disrupt cancer cell division, however it is not currently approved in children. Evidence shows that ion channels not only regulate electrical signalling of excitable cells, but also play a crucial role in the development and progression of brain tumours, essential in cell cycle control and therefore presenting as valuable therapeutic targets. Candidate ion channel genes (ICG) associated with the malignant status of high-grade glioma (HGG) were identified via multivariate analysis of in-house and publicly available data sets. RNA sequencing of in-house patient tissues revealed an increased expression of CLIC1 and CLIC4, with pHGG exhibiting increased expression at protein and RNA levels in both the Paugh data set and in-house primary cell lines and TMAs. Clinical correlation determined that CLIC4 and CLIC1 deficiency was associated with increased overall survival (p=<0.03). siRNA depletion of CLIC1 and CLIC4 propagated a reduction in the proliferation, migration and invasion of pHGG cell lines and resulted in cell cycle arrest. Furthermore, CLIC1 and CLIC4 deficiency exacerbated the killing capacity of TT fields. Whole transcriptome gene expression analysis (Human Clairom™ Array) of paediatric GBM cell lines treated with tumour treating fields and found that cells treated with TTfields exhibited a down-regulation in CLIC1 and CLIC4 compared to untreated cells. These data provide rationale that genetic, electrical, and pharmacological manipulation of ion channels will reduce the capacity of childhood brain tumours to proliferate and invade. Therefore, may be a suitable target for combination therapy to enhance the treatment efficacy of TTfields and help bring this non-invasive therapy to paediatric patients.