Abstract 2315: Synergic antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 (CLIC1) inhibition in human glioblastoma primary culture

Abstract

Abstract Glioblastoma relapse inevitably occurs in the majority of patients after surgery. Chemo- and radio- therapy are in most cases ineffective, while Tumor Treating Fields (TTFields) therapy delays average tumor recurrence by a few months. It is widely accepted that tumor reappearance is a result of the proliferation of residual glioblastoma stem cell (GSC) subpopulation, which escaped surgery. Long-term TTFields stimulation in in vitro experiments mimic glioblastoma cells recrudescence. After the first three days of TTFields exposure, cell growth is totally inhibited. However, in prolonged experiments, despite the chronic presence of TTFields stimulation, glioblastoma cells reestablish the ability to proliferate, even if at low rate. At the end of twelve days, exponentially growing cells show an increase of stemness markers, a drop of the membrane resistance with a related increase of membrane current, and an average depolarized membrane potential. Twelve days of TTFields treatment resulted in progressive increase in GSCs in the tumor cell population from 10% to more than 30%. Our long-term goal is to improve TTFields antitumoral activity by linking brain stimulation with a pharmacological strategy targeting GSC proliferation. The objective of our study is to test the therapeutic potential of combining TTFields exposure with the inhibition of the protein transmembrane Chloride Intracellular Channel 1 (tmCLIC1), which is crucial for GSCs proliferation. tmCLIC1 activity increases under oxidative stress conditions. Preliminary experiments using the INOVITRO-LIVE system showed a cytoplasmic oxidation increase under acute TTFields stimulation. tmCLIC1 impairment by ion channel specific antagonists affected the G1/S checkpoint and hence, tumor cell proliferation. Targeting synergically different glioblastoma cell cycle checkpoints, G2/M with TTFields stimulation and G1/S with tmCLIC1 inhibition, would include the vast majority of glioblastoma cell population. Combination TTFields exposure and tmCLIC1 ion channel inhibition could represent an efficacious step forward in the treatment of glioblastoma. Citation Format: Michele Mazzanti, Stefania Castiglione, Matteo Ranucci, Gaetano Cannavale, Francesca Cianci, Ivan Verduci. Synergic antitumoral activity of TTFields stimulation and Chloride Intracellular Channel 1 (CLIC1) inhibition in human glioblastoma primary culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2315.