An overview of potential novel mechanisms of action underlying Tumor Treating Fields-induced cancer cell death and their clinical implications

Abstract

Traditional cancer therapy choices for clinicians are surgery, chemotherapy, radiation and immune therapy which are used either standalone therapies or in various combinations. Other physical modalities beyond ionizing radiation include photodynamic therapy and heating and the more recent approach referred to as Tumor Treating Fields (TTFields). TTFields are intermediate frequency, low-intensity, alternating electric fields that are applied to tumor regions and cells using noninvasive arrays. TTFields have revolutionized the treatment of newly diagnosed and recurrent glioblastoma (GBM) and unresectable and locally advanced malignant pleural mesothelioma (MPM). TTFields are thought to kill tumor cells predominantly by disrupting mitosis; however it has been shown that TTFields increase efficacy of different classes of drugs, which directly target mitosis, replication stress and DNA damage pathways. Hence, a detailed understanding of TTFields’ mechanisms of action is needed to use this therapy effectively in the clinic. Recent findings implicate TTFields’ role in different important pathways such as DNA damage response and replication stress, ER stress, membrane permeability, autophagy, and immune response. This review focuses on potentially novel mechanisms of TTFields anti-tumor action and their implications in completed and ongoing clinical trials and pre-clinical studies. Moreover, the review discusses advantages and strategies using chemotherapy agents and radiation therapy in combination with TTFields for future clinical use.

Keywords:

• TTFields
• GBM
• DNA damage
• replications tress
• novel combination therapy

Acknowledgements

The authors thank Dr. Jonathan Feinberg and Dr. Damiana Chiavolini for editing the manuscript.

Disclosure statement

MDS was the recipient of a sponsored research agreement from Novocure Ltd. MDS is also the recipient of AACR- Novocure Tumor Treating Fields research grant. NKK is the recipient of AACR-Novocure Career development award for Tumor Treating Fields research. MDS and NKK received travel grants to attend conferences. NKK and MDS are listed as inventors on US patent applications entitled ‘Treating tumors using Tumor Treating Fields combined with a PARP inhibitor’ filed 28 March 2018 and which is pending final approval as well as a provisional patent entitled ‘Combination therapeutics using Tumor Treating Fields’ filed 23 March 2020.

Additional information

Funding

This work was supported by American Association for Cancer Research.

Notes on contributors

Narasimha Kumar Karanam

Narasimha Kumar Karanam received his master’s degree in biochemistry from the University of Hyderabad, India. He subsequently pursued his PhD in cancer biology at the University of Greifswald, Germany, with Professor Uwe Volker. Later he joined as a postdoctoral fellow in Dr. Michael Story’s laboratory at UT Southwestern Medical Center, Dallas and currently he is an instructor.

Michael D. Story

Michael D. Story recieved his PhD at Colorado State University in 1989. He was a post-doctoral fellow in the laboratory of Dr. Ray Meyn at the MD Anderson Cancer Center for 3 years before his promotion to faculty. In 2004, he moved to UT Southwestern Medical Center as an Associate Professor, ultimately rising to Professor. He is currently vice-Chair of the Department of Radiation Oncology, Chief of the Division of Molecular Radiation Biology and Director of the UTSW Pre-Clinical Radiation Core Facility. Dr. Story holds the David A. Pistenmaa MD, PhD Distinguished Chair in Radiation Oncology. He is a member of the National Council of Radiation Protection and Measurements and serves as a member of the Board of Directors. He is an Associate Editor for the International Journal of Particle Therapy and Senior Editor for Mutagenesis.