Therapeutic potential of tumor treating fields for malignant brain tumors

Abstract

Background Malignant brain tumors are among the most threatening diseases of the central nervous system, and despite increasingly updated treatments, the prognosis has not been improved. Tumor treating fields (TTFields) are an emerging approach in cancer treatment using intermediate‐frequency and low‐intensity electric field and can lead to the development of novel therapeutic options. Recent Findings A series of biological processes induced by TTFields to exert anti‐cancer effects have been identified. Recent studies have shown that TTFields can alter the bioelectrical state of macromolecules and organelles involved in cancer biology. Massive alterations in cancer cell proteomics and transcriptomics caused by TTFields were related to cell biological processes as well as multiple organelle structures and activities. This review addresses the mechanisms of TTFields and recent advances in the application of TTFields therapy in malignant brain tumors, especially in glioblastoma (GBM). Conclusions As a novel therapeutic strategy, TTFields have shown promising results in many clinical trials, especially in GBM, and continue to evolve. A growing number of patients with malignant brain tumors are being enrolled in ongoing clinical studies demonstrating that TTFields‐based combination therapies can improve treatment outcomes.

Enhancing glioblastoma treatment through the integration of tumor-treating fields

“…The mechanisms of autophagy associated with the action of TTFields are mostly associated with cellular stress ( 10 – 12 , 14 , 15 ) or with the activation of programmed cell death pathways ( 14 ). RNA analysis revealed a >2 fold increase in autophagy-related genes in TTField-treated cells.…”

“…When high-pulsed electric fields are applied to cells, they may directly or indirectly increase membrane permeability. This mechanism is important because it is observed only in cancer cells and not in healthy cells ( 15 ). As TTFields also increase tumor cell membrane permeability without affecting normal cell membranes, demonstrating the selective action of TTFields on cancer cells, shorter treatment durations have minimal effects on normal cells ( 11 ).…”

“…In turn, the pharmacodynamic derivative effects of the use of TTFields are associated with the loss of cell membrane tightness ( 10 , 14 , 15 ). They allow transmembrane transport of substances up to a certain size, affecting ion channels such as CACNA1C, influencing cell cycle progression and migration, altering cell membrane potential and intracellular ion homeostasis, and disrupting tight junction proteins of the blood-brain barrier, temporarily increasing its permeability and expanding the potential for intracranial drug applications ( 15 , 16 ). TTFields exposure results in reversible changes in membrane permeability, with the cell membrane integrity being repairable ( 11 ).…”

“…Thus, TTFields seem to universally inhibit the metastatic spread of tumors by hindering cancer cell motility, suppressing ciliogenesis, affecting EMT-related biomarkers, inhibiting ECM degradation, reducing angiogenesis, and inhibiting PI3K/AKT and MAPK signaling pathways. Ultimately, this leads to reduced migration, invasion, and aggressive properties of cancer cells ( 14 , 15 , 17 ).…”

“…Immunomodulation is a relatively poorly understood mechanism of action of TTFields, although some studies have shown its high potential to enhance immune responses in cancer treatment ( 10 , 11 , 15 ). While in cancer cells TTFields exposure downregulates the MAPK and NF-κB pathways, an opposite effect is observed in mouse macrophages, where TTFields increases the phos-phorylation of IκBα and NF-κB p65, triggering the release of phosphorylated p65.…”