CSIG-26. IS INTRINSIC APOPTOSIS THE SIGNALING PATHWAY ACTIVATED BY TUMOR-TREATING FIELDS FOR GLIOBLASTOMA?

Abstract

Abstract Increasingly, tumor-treating fields (TTFields, 2 V/cm, 200 kHz) are accepted as the fourth treatment modality for glioblastoma. Evidence shows that substituting non-steroidal inflammation control (celecoxib) for dexamethasone increases overall survival from 4.8 to 11.0 months, and more recently, up to 60 months. Toward explaining TTFields mechanism of action (MoA), our numerical simulations indicate that TTFields disrupt functionality of microtubules, which in turn trigger the intrinsic apoptotic pathway independent of cell cycle checkpoints. We present the theory and empirical evidence. 1) TTFields act similarly to chemotherapeutic ‘spindle poisons’ by interfering with microtubule (MT) polymerization, increasing free tubulin by 20% in relative terms; 2) Finite element modeling shows TTFields amplify electric field strength, in accord with empirical results, a) along the MT when aligned with the cell axis, where field strength exceeds 10–16 N required to disrupt motor protein transit, and b) 15x at MT ends when orthogonal to cell axis; 3) Either through producing excess free tubulin, which may block voltage-dependent anion channels, or direct effects on the mitochondrial inner and outer membranes, TTFields inhibit expression of pro-survival protein Bcl-2; 4) Decreased Bcl-2 expression activates the intrinsic apoptotic pathway in a novel cell-cycle-checkpoint and caspase-independent manner; 5) Patients using low (< 4.1 mg/day) vs. high (>4.1 mg/day) dexamethasone doses experienced an average 8.7 vs. 3.2 months OS and up to 60 months; 6) Numerous studies in both brain and other tissues show that dexamethasone a) promotes extrinsic, immune-system apoptosis and b) inhibits intrinsic, Bcl-2/Bax mediated apoptosis; 7) Downstream effects of intrinsic apoptosis are remarkably similar to empirically-observed effects of TTFields on tumor cells. Research supported by Novocure Ltd. Dept of Neurosurgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston MA USA. carlsokw@bidmc.harvard.edu. Dept of Physics, University of Alberta, Edmonton, Canada, Novocure Ltd., Haifa, Israel.