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Tumor treating fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the treatment of glioblastoma multiforme and mesothelioma, and they are currently under study in many other cancer types. While antimitotic effects were the first recognized biological anticancer activity of TTFields, data have shown that tumor treating fields achieve their anticancer effects through multiple mechanisms of action. TTFields therefore have the ability to be useful for many cancer types in combination with many different treatment modalities. Here, we review the current understanding of TTFields and their mechanisms of action.

Why Is 4 V/cm Electric Field Strength Necessary for Maximum Tumor-Treating Fields Efficacy? INTRODUCTION: Tumor Treating Fields (TTFields) extend overall survival in glioblastoma patients. Threshold field strength for TTFields is typically cited as 2V/cm. Yet plots of cell death vs. field strength in vitro indicate a power law relationship asymptotic to 4 V/cm for 100% efficacy. The mechanisms of action (MoA) of TTFields underlying this relationship are currently under investigation. TTFields are suspected of disrupting critical mitotic processes performed by large polar cellular molecules such as microtubules (MT). METHODS: Using the power law relationship for the energy (intensity, I) carried by an electric field and its amplitude (Eq. 1), we calculated energy vs. TTFields amplitude. (1) RESULTS: We suggest Eq. 1 is a likely source of the relationship between TTFields' amplitude and cell death proportion that has been demonstrated empirically. Further, Table 1 shows energy transmitted per unit MT surface area per TTFields cycle, specifically, the energy per MT dimer band around an MT helix per TTFields period of 5 µs. TTFields Field Strength (V/cm)Radiant Flux Density (W/nm2)Energy/(Cycle-Area) (J/nm2)Energy/MT Dimer/Cycle (J)Energy/MT Dimer Band/Cycle (J)113.3 × 10−186.63 × 10−234.01 × 10−224.17 × 10−20253.1 × 10−1826.6 × 10−231.60 × 10−211.67 × 10−193119 × 10−1859.7 × 10−233.61 × 10−213.75 × 10−194212 × 10−18106 × 10−236.42 × 10−216.67 × 10−195332 × 10−18166 × 10−231.00 × 10−201.04 × 10−186478 × 10−18239 × 10−231.44 × 10−201.50 × 10−18 A metric for disruption of cellular processes is 1-2 orders of magnitude greater than the thermal background energy in the cell, kT = 4.3 × 10−21 J. Table 1 shows that the energy absorbed by a MT dimer is insufficient to disrupt cellular processes at 2 V/cm, while due to energy increasing with square of field strength, at 5 V/cm it may be disruptive. For an entire dimer band around the MT helix, 2 V/cm appears to be sufficient, while 4 V/cm seems amply strong to disrupt MT function, in accordance with in vitro experiments. CONCLUSION: Assuming the power law of energy vs. electric field strength and the resulting energy absorbed by microtubule components, we found a correlation between typical TTFields' amplitudes and estimated disruption thresholds of MT function. TTFields MoA. 4 V/cm, not 2V/cm, should be the target field strength to realize the full efficacy of TTFields. Citation Format: Kristen W. Carlson, Jack A. Tuszynski, Socrates Dokos, Nirmal Paudel, Zeev Bomzon. What electric field strength is necessary for maximum tumor-treating fields efficacy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 472.

Tumor Treating Fields (TTFields) have become a fourth modality for cancer treatment. Mild electric fields (~1-4 V/cm) produce few side effects and significantly extend overall survival of glioblastoma patients, and TTFields are in clinical trials for a variety of tumor cell types. Our goal is to uncover TTFields’ mechanism and cell signaling pathways by numerically modeling their effects on sub-cellular structures, such as microtubules (MTs) and their interactions with motor proteins. METHODS: We have built finite element models in COMSOL Multiphysics (tm) of the MT and its micro-environment to test hypotheses on TTFields’ mechanism of action by predicting effects on sub-cellular structures. RESULTS: One model prediction is that current density induced in the MT counter-ion layer by TTFields essentially shunts electric current within them. The strongest current flows through the counter-ion layer surrounding the MT’s C-termini and energy density in this layer likely exceeds the level to disrupt motor protein ‘walk’ along the MT. The energy density is predicted at 10-20 Joules when both the field and the MTs are aligned with the cell axis. A second mechanism examined by our model is disruption of the ‘foot’ of kinesin, released from its C-terminus contact by ATP (10-19 Joules). The final phase of the walk is driven by thermal buffeting of the forward foot randomly positioning it near enough to the C-terminus for electrostatic forces to bind it. A stall force ~10-19 - 10-16 N from TTFields would prevent diffusion and disrupt the kinesin walk. A recent clinical study segregating patient cohorts treated vs. not treated with dexamethasone found overall survival indefinitely for the non-dexamethosone cohort, leading us to hypothesize that TTFields activate the intrinsic Bcl2-mediated apoptotic signaling pathway. Future modeling will seek to tie disruption of motor protein transport along MTs to activating intrinsic apoptosis, e.g. via failure to silence the G2 cell cycle checkpoint. CONCLUSION: Our modeling predicts that TTFields in cytosol induce electric currents along MTs that are strong enough to disrupt key cellular functions such as the kinesin walk and C-termini transitions, both of which are crucial for motor protein transport. Hence, TTFields disrupt the most delicate mechanisms involved in the carefully-orchestrated succession of steps in mitosis. Citation Format: Kristen W. Carlson, Nirmal Paudel, Jack A. Tuszynski, Zeev Bomzon. Numerical simulation of tumor treating fields effects on cell structures: Mechanism and signaling pathway candidates [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3725.

Tumor Treating Fields (TTFields) are 100-500 kHz electric fields with intensities of about 1-4 V/cm. They are known to exert an antimitotic effect on cancer cells, most likely by exerting forces on highly polar tubulin dimers, thereby disrupting spindle formation. Calculations show that TTFields-tubulin interaction energy is negligible compared to the thermal energy in the cell (1). Therefore, this interaction is unlikely to disrupt cellular function. Conductivity of polymerized tubulin, microtubules (MTs), was measured to be 20 S/m, which is 400 times higher than that of the ambient cytosol (0.05 S/m) (2). Thus when TTFields penetrate the cytosol, they may induce electric currents along MTs that are strong enough to disrupt key cellular functions. In particular, if the power (energy per unit time) deposited by these currents is on par with that the power consumed by the molecular motor kinesin, then TTFields may disrupt the forces needed for cell division, thereby disrupting mitosis. To test this hypothesis, we performed numerical simulations evaluating the magnitude of the electric current along MTs exposed to TTFields at 200 kHz. Based on studies of MTs and their microenvironment, we model the MT as a layered cylindrical structure (1): Innermost is the lumen (15 nm in thickness), surrounded by 13 strands of alpha-beta tubulin dimers linked in a helix (4.5 nm). C-termini extend out from the helix with a thickness of 3.5 nm. MTs carry net negative charge; thus they are surrounded by a counter-ion layer (2 nm), and an outer nonconductive Bjerrum layer (3 nm). We built a finite element model in COMSOL Multiphysics (tm) incorporating these layers and examined the current density induced in each layer by TTFields for MTs varying in length from 1-10 µm within an ambient 200 kHz AC electric field of 1-4 V/cm. Our model shows that MTs act as electrical "shunts" that conduct electric current within them. The highest current flows through the counter-ion layer surrounding the C-termini. The current density in this layer exceeds the level likely to disrupt the motor protein kinesin "walk" along the C-termini. The current density is highest when both the field and the MTs are aligned with the cell axis, in accord with in vitro experiments (3). Our model is consistent with the hypothesis that when cells are exposed to TTFields, MTs act as cables carrying high-density electric currents strong enough to disrupt the function of molecular motors, ultimately disrupting mitosis. References: 1. Tuszynski JA et al. An overview of sub-cellular mechanisms involved in the action of TTFields. Int J Environ Res Public Health 2016. 2. Santelices IB et al. Response to alternating electric fields of tubulin dimers and microtubule ensembles in electrolytic solutions. Sci Rep 2017. 3. Kirson ED et al. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Proc Natl Acad Sci U S A 2007. Citation Format: Kristen W. Carlson, Jack A. Tuszynski, Socrates Dokos. Numerical modeling of intracellular mechanisms in tumor-treating fields [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3209.