Luke Frizzell

Background: Glioblastomas are the most common and aggressive of the malignant primary brain tumors.¹ Glioblastomas can arise anywhere in the central nervous system and can manifest with multiple and intricate forms of neoplasms presenting with varying genetic abnormalities and behaviors.^2,3 These complexities make treatment very difficult. Some of the traditional and common treatments for glioblastoma are surgical removal, radiation therapy, and chemotherapy.¹ Tumor Treatment Fields were approved for the treatment of glioblastomas in 2011.⁴ This device includes transducer arrays that are applied to the patient’s scalp to transmit electric fields to tumors.⁴ Tumor Treatment Fields have multiple mechanisms of action. Most studies explore its effect on tubulin dynamics and the subsequent inhibition of the spindle assembly checkpoint, but there are newer studies coming out investigating novel mechanisms of Tumor Treatment Fields including its reduction in circMMD and increasing the permeability of the cellular membrane.^5-8

Objectives: In this narrative review, we explored the mechanisms by which tumor treatment fields can treat glioblastomas and its possible synergistic effect with other treatment modalities.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the following keywords: “glioblastoma”. “tumor treatment field”, and/or “electric field”.

Results: The deviation of tubulin’s structure is one way that tumor treatment fields inhibit tumor growth.⁵ While rigid structures like alpha helices and beta sheets remained mostly unchanged to electric field exposure, the more flexible motifs such as coils, hydrogen-bonded turns and 3₁₀ helices showed a much higher deviation.⁵ Furthermore, Tumor treatment fields can slow glioblastoma growth by disrupting cell division via the inhibition of spindle fiber formation.⁶ There was a synergistic anti-proliferative effect found when using tumor treatment fields and spindle checkpoint inhibitors concurrently.⁶ Also, tumor treatment fields can suppress glioma growth by inhibiting Wnt/B-catenin signaling through novel mechanisms: the suppression of circMMD, sequestration of DLV1 transcription factors, and degradation of FZD6 transcripts by miR-15Bb-5p.⁷ Finally, there is evidence that the cellular membrane permeability increases in the presence of tumor treatment field exposure with both an increase in the number and size of perforations on the membrane.⁸

Conclusion: Tumor Treatment fields offer multiple mechanisms for inhibiting glioblastoma growth. These diverse mechanisms create the potential for concurrent treatment with other modalities, presenting a promising therapeutic approach and a pathway that future research can explore. Tumor treatment fields demonstrate synergistic effects with chemotherapy by increasing cellular permeability and thus facilitating easier entry of chemotherapeutic agents into the cell.⁸ Additionally, Tumor Treatment Fields exhibit synergy with spindle checkpoint inhibitors.⁶ Another study has shown a synergistic effect with chemoradiation, although further research is necessary to clarify the mechanistic basis behind this interaction.⁹ Continued research into the molecular mechanisms of tumor treatment fields and their interaction with other therapies is essential for optimizing their clinical utility and improving outcomes for patients with glioblastoma.

Works Cited:

1. Schaff LR, Mellinghoff IK. Glioblastoma and Other Primary Brain Malignancies in Adults: A Review. JAMA. 2023;329(7):574-587.
2. Lopes Abath Neto O, Aldape K. Morphologic and Molecular Aspects of Glioblastomas. Neurosurg Clin N Am. 2021;32(2):149-158.
3. McKinnon C, Nandhabalan M, Murray SA, Plaha P. Glioblastoma: clinical presentation, diagnosis, and management. BMJ. 2021;374:n1560. Published 2021 Jul 14.
4. Fabian D, Guillermo Prieto Eibl MdP, Alnahhas I, Sebastian N, Giglio P, Puduvalli V, Gonzalez J, Palmer JD. Treatment of Glioblastoma (GBM) with the Addition of Tumor-Treating Fields (TTF): A Review. Cancers. 2019; 11(2):174.
5. Timmons JJ, Preto J, Tuszynski JA, Wong ET. Tubulin’s response to external electric fields by molecular dynamics simulations. PLoS One. 2018;13(9):e0202141. Published 2018 Sep 19.
6. Kessler AF, Frömbling GE, Gross F, et al. Effects of tumor treating fields (TTFields) on glioblastoma cells are augmented by mitotic checkpoint inhibition [published correction appears in Cell Death Discov. 2019 Jul 10;5:116]. Cell Death Discov. 2018;4:12. Published 2018 Jul 16.
7. Xu S, Luo C, Chen D, et al. circMMD reduction following tumor treating fields inhibits glioblastoma progression through FUBP1/FIR/DVL1 and miR-15b-5p/FZD6 signaling. J Exp Clin Cancer Res. 2023;42(1):64. Published 2023 Mar 17.
8. Chang E, Patel CB, Pohling C, et al. Tumor treating fields increases membrane permeability in glioblastoma cells. Cell Death Discov. 2018;4:113. Published 2018 Dec 5.
9. Ali AS, Lombardo J, Niazi MZ, et al. Concurrent chemoradiation and Tumor Treating Fields (TTFields, 200 kHz) for patients with newly diagnosed glioblastoma: patterns of progression in a single institution pilot study. J Neurooncol. 2022;160(2):345-350.