Development and validation of a comprehensive tumor treating fields system for glioblastoma therapy: From prototype design to preclinical evaluation

Abstract

Glioblastoma multiforme (GBM) is an aggressive and lethal brain tumor with limited treatment options and poor prognosis. Standard therapies such as surgery, radiation, and chemotherapy provide modest survival benefits but are often ineffective against tumor recurrence. Tumor treating fields (TTF) therapy has emerged as a promising non-invasive treatment modality that uses alternating electric fields to disrupt cancer cell division and inhibit tumor growth. However, the optimization and practical implementation of TTF systems remain challenging due to limitations in field penetration, electrode design, and treatment efficacy. In this study, we designed and developed a novel TTF prototype system to enhance electric field transmission and optimize therapeutic efficiency. The system incorporates high-dielectric ceramic electrodes made of barium titanate zirconate, allowing for superior field penetration. We evaluated the system through a series of in vitro and in vivo experiments. In vitro, GBM cells exposed to the TTF system exhibited significant reductions in proliferation, with higher field intensities yielding greater inhibition. In vivo, using a rat GBM model, we observed marked tumor suppression, as validated by bioluminescence imaging and magnetic resonance imaging. Survival analysis further demonstrated prolonged lifespan in TTF-treated rats compared to controls. Our findings highlight the potential of this novel TTF system to improve GBM treatment outcomes. This study provides a comprehensive framework for future advancements in TTF therapy, paving the way for clinical translation and further integration with conventional and emerging cancer therapies.

Keywords

Glioblastoma multiforme / Tumor therapy / Tumor treating fields / Electric field therapy / System design

Acknowledgments

None.

Funding

This research was supported by National Natural Science Foundation of China (52302118), Fundamental Research Funds for the Central Universities, Sun Yat-sen University (24qnpy312), and Zhejiang Provincial Natural Science Foundation of China under Grant No. LQ23B050006.

Conflict of interest

The authors declare that they have no competing interests.

Author contributions

Conceptualization: Zhiyong Wang

Formal analysis: Han Lv

Investigation: Xindong Wang

Methodology: Xindong Wang

Writing-original draft: Xindong Wang

Writing-review & editing: Han Lv, Xian Wang

Ethics approval and consent to participate

The study is approved by Ethics Review Committee of Hangzhou Yanqu Information Technology Co., Ltd. (approval no.: 202404A010).

Consent for publication

Not applicable.

Availability of data

All datasets on which the conclusions of this paper rely have been presented in the main manuscript.

References

[1] Yalamarty S, Filipczak N, Li, X, et al. Mechanisms of resistance and current treatment options for glioblastoma multiforme (GBM). Cancers (Basel). 2023; 15(7):2116. doi: 10.3390/cancers15072116

[2] Saqib M, Zahoor A, Rahib A, et al. Clinical and translational advances in primary brain tumor therapy with a focus on glioblastoma-A comprehensive review of the literature. World Neurosurg X. 2024;24:100399.doi: 10.1016/j.wnsx.2024.100399

[3] Stupp R, Taillibert S, Kanner A, et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: A randomized clinical trial. JAMA. 2017; 318(23):2306-2316.doi: 10.1001/jama.2017.18718

[4] Stupp R, Wong E, Kanner A, et al. NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer. 2012; 48(14):2192-2202.doi: 10.1016/j.ejca.2012.04.011

[5] Wong E, Lok E, Swanson K. Clinical benefit in recurrent glioblastoma from adjuvant NovoTTF-100A and TCCC after temozolomide and bevacizumab failure: A preliminary observation. Cancer Med. 2015; 4(3):383-391.doi: 10.1002/cam4.421

[6] Kirson E, Dbalý V, Tovarys F, et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A. 2007; 104(24): 10152-10157.doi: 10.1073/pnas.0702916104

[7] Warren K, Liu L, Liu Y, et al. The impact of timing of concurrent chemoradiation in patients with high-grade glioma in the era of the stupp protocol. Front Oncol. 2019;9:186.doi: 10.3389/fonc.2019.00186

[8] Pless M, Weinberg U. Tumor treating fields: Concept, evidence and future. Expert Opin Investig Drugs. 2011; 20(8):1099-1106.doi: 10.1517/13543784.2011.583236

[9] Gutin P, Wong E. Noninvasive application of alternating electric fields in glioblastoma: A fourth cancer treatment modality. Am Soc Clin Oncol. 2012; 32:126-131.doi: 10.14694/EdBook_AM.2012.32.122

[10] Cao Q, Hajosch A, Kast R, et al. Tumor Treating Fields (TTFields) combined with the drug repurposing approach CUSP9v3 induce metabolic reprogramming and synergistic anti-glioblastoma activity in vitro. Br J Cancer. 2024; 130(8):1365-1376.doi: 10.1038/s41416-024-02608-8

[11] Rominiyi O, Vanderlinden A, Clenton S, et al. Tumour treating fields therapy for glioblastoma: Current advances and future directions. Br J Cancer. 2021; 124(4):697-709. doi: 10.1038/s41416-020-01136-5

[12] Stupp R, Taillibert S, Kanner A, et al. Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: A randomized clinical trial. JAMA. 2015; 314(23):2535-2543.doi: 10.1001/jama.2015.16669

[13] Guo X, Yang X, Wu J, et al. Tumor-treating fields in glioblastomas: Past, present, and future. Cancers (Basel). 2022; 14(15):3669.doi: 10.3390/cancers14153669

[14] Moser J, Salvador E, Deniz K, et al. The mechanisms of action of tumor treating fields. Cancer Res. 2022; 82(20):3650-3658. doi: 10.1158/0008-5472.Can-22-0887

[15] Voloshin T, Schneiderman R, Volodin A, et al. Tumor treating fields (TTFields) hinder cancer cell motility through regulation of microtubule and acting dynamics. Cancers (Basel). 2020; 12(10):3016.doi: 10.3390/cancers12103016

[16] Chen W, Wang Y, Zhao B, et al. Optimal therapies for recurrent glioblastoma: A Bayesian network meta-analysis. Front Oncol. 2021;11:641878.doi: 10.3389/fonc.2021.641878

[17] Taphoorn M, Dirven L, Kanner A, et al. Influence of treatment with tumor-treating fields on health-related quality of life of patients with newly diagnosed glioblastoma: A secondary analysis of a randomized clinical trial. JAMA Oncol. 2018; 4(4):495-504.doi: 10.1001/jamaoncol.2017.5082

[18] Fabian D, Guillermo M, Alnahhas I, et al. Treatment of glioblastoma (GBM) with the addition of tumor-treating fields (TTF): A review. Cancers. 2019; 11(2):174.doi: 10.3390/cancers11020174

[19] Mun E, Babiker H, Weinberg U, et al. Tumor-treating fields: A fourth modality in cancer treatment. Clin Cancer Res. 2018; 24(2):266-275.doi: 10.1158/1078-0432.CCR-17-1117

[20] Anadkat M, Lacouture M, Friedman A, et al. Expert guidance on prophylaxis and treatment of dermatologic adverse events with Tumor Treating Fields (TTFields) therapy in the thoracic region. Front Oncol. 2022;12:975473. doi: 10.3389/fonc.2022.975473

[21] Pan J, Eskandar T, Ahmed Z, et al. Biophysical and biological mechanisms of tumor treating fields in glioblastoma. J Cancer Sci Clin Ther. 2024; 8(3):265-270.doi: 10.26502/jcsct.5079249

[22] Berkelmann L, Bader A, Meshksar S, et al. Tumour-treating fields (TTFields): Investigations on the mechanism of action by electromagnetic exposure of cells in telophase/cytokinesis. Sci Rep. 2019; 9(1):7362.doi: 10.1038/s41598-019-43621-9

[23] Li X, Yang F, Rubinsky B. A theoretical study on the biophysical mechanisms by which tumor treating fields affect tumor cells during mitosis. IEEE Trans Biomed Eng. 2020; 67(9):2594-2602.doi: 10.1109/TBME.2020.2965883

[24] Farmani A, Mahdavinezhad F, Scagnolari C, et al. An overview on tumor treating fields (TTFields) technology as a new potential subsidiary biophysical treatment for COVID-19. Drug Deliv Transl Res. 2022; 12(7):1605-1615. doi: 10.1007/s13346-021-01067-5

[25] Carrieri F, Smack C, Siddiqui I, et al. Tumor treating fields: At the crossroads between physics and biology for cancer treatment. Front Oncol. 2020;10:575992.doi: 10.3389/fonc.2020.575992

[26] Xiang X, Liu H, Tao X, et al. Glioblastoma behavior study under different frequency electromagnetic field. iScience. 2023; 26(12):108575.doi: 10.1016/j.isci.2023.108575

[27] Tewatia K, Sharma A, Sharma M, et al. Factors affecting morphological and electrical properties of Barium Titanate: A brief review. Mater Today Proc. 2021; 44:4548-4556. doi: 10.1016/j.matpr.2020.10.813

[28] Liu W, Kong F, Liang Y, et al. Strategy to achieve both enhanced dielectric tunability and reduced dielectric loss in the barium zirconium titanate ceramics. Ceram Int. 2024; 50(18):31759-31766.doi: 10.1016/j.ceramint.2024.05.354

[29] Sumona H, Sultan M, Urmi S, et al. Investigation of structural, electrical and optical properties of lanthanum and zirconium doped barium titanate ceramics. Mater Sci Eng B. 2023;298:116844.doi: 10.1016/j.mseb.2023.116844

[30] Barsheshet Y, Voloshin T, Brant B, et al. Tumor treating fields (TTFields) concomitant with immune checkpoint inhibitors are therapeutically effective in non-small cell lung cancer (NSCLC) in vivo model. Int J Mol Sci. 2022; 23(22):14073. doi: 10.3390/ijms232214073

[31] Pless M, Droege C, von Moos R, et al. A phase I/II trial of tumor treating fields (TTFields) therapy in combination with pemetrexed for advanced non-small cell lung cancer. Lung Cancer. 2013; 81(3):445-450.doi: 10.1016/j.lungcan.2013.06.025

[32] Giladi M, Schneiderman R, Porat Y, et al. Mitotic disruption and reduced clonogenicity of pancreatic cancer cells in vitro and in vivo by tumor treating fields. Pancreatology. 2014; 14(1):54-63.doi: 10.1016/j.pan.2013.11.009

[33] Jo Y, Oh G, Gi Y, et al. Tumor treating fields (TTF) treatment enhances radiation-induced apoptosis in pancreatic cancer cells. Int J Radiat Biol. 2020; 96(12):1528-1533.doi: 10.1080/09553002.2020.1838658

[34] Vergote I, von Moos R, Manso L, et al. Tumor treating fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study. Gynecol Oncol. 2018; 150(3):471-477.doi: 10.1016/j.ygyno.2018.07.018

[35] Lok E, San P, White V, et al. Tumor treating fields for ovarian carcinoma: A modeling study. Adv Radiat Oncol. 2021; 6(4):100716.doi: 10.1016/j.adro.2021.100716

[36] Wu H, Yang L, Liu H, et al. Exploring the efficacy of tumor electric field therapy against glioblastoma: An in vivo and in vitro study. CNS Neurosci Ther. 2021; 27(12):1587-1604.doi: 10.1111/cns.13750

[37] Wu H, Wang C, Liu J, et al. Evaluation of a tumor electric field treatment system in a rat model of glioma. CNS Neurosci Ther. 2020; 26(11):1168-1177.doi: 10.1111/cns.13441