Biological activity of tumor-treating fields in preclinical glioma models
Manuela Silginer, Michael Weller, Roger Stupp, Patrick Roth, Manuela Silginer, Michael Weller, Roger Stupp, Patrick Roth
Abstract
Glioblastoma is the most common and aggressive form of intrinsic brain tumor with a very poor prognosis. Thus, novel therapeutic approaches are urgently needed. Tumor-treating fields (TTFields) may represent such a novel treatment option. The aim of this study was to investigate the effects of TTFields on glioma cells, as well as the functional characterization of the underlying mechanisms. Here, we assessed the anti-glioma activity of TTFields in several preclinical models. Applying TTFields resulted in the induction of cell death in a frequency- and intensity-dependent manner in long-term glioma cell lines, as well as glioma-initiating cells. Cell death occurred in the absence of caspase activation, but involved autophagy and necroptosis. Severe alterations in cell cycle progression and aberrant mitotic features, such as poly- and micronucleation, preceded the induction of cell death. Furthermore, exposure to TTFields led to reduced migration and invasion, which are both biological hallmarks of glioma cells. The combination of TTFields with irradiation or the alkylating agent, temozolomide (TMZ), resulted in additive or synergistic effects, and the O6-methyl-guanine DNA methyltransferase status did not influence the efficacy of TTFields. Importantly, TMZ-resistant glioma cells were responsive to TTFields application, highlighting the clinical potential of this therapeutic approach. In summary, our results indicate that TTFields induce autophagy, as well as necroptosis and hamper the migration and invasiveness of glioma cells. These findings may allow for a more detailed clinical evaluation of TTFields beyond the clinical data available so far.
Conflict of interest statement
MW has received research grants from Actelion, Alpinia Institute, Bayer, Isarna, MSD, Merck Serono, Piqur and Roche and honoraria for lectures or advisory board participation from Celldex, Isarna, Magforce, MSD, Merck Serono, Pfizer, Roche and Teva. RS is the principal investigator for the pivotal clinical trials on TTFields in newly diagnosed and recurrent glioblastoma. RS served as an advisor to Novocure (non-remunerated), and has received travel assistance for trial associated activities, data review and data presentation at scientific meetings. PR has received honoraria for advisory boards and lectures from BMS, Roche, MSD, Novartis and Molecular Partners. MS declares no conflict of interest.
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Source: PubMed