An Overview of Alternating Electric Fields Therapy (NovoTTF Therapy) for the Treatment of Malignant Glioma

Abstract

As with many cancer treatments, tumor treating fields (TTFields) target rapidly dividing tumor cells. During mitosis, TTFields-exposed cells exhibit uncontrolled membrane blebbing at the onset of anaphase, resulting in aberrant mitotic exit. Based on these criteria, at least two protein complexes have been proposed as TTFields' molecular targets, including α/β-tubulin and the septin 2, 6, 7 heterotrimer. After aberrant mitotic exit, cells exhibited abnormal nuclei and signs of cellular stress, including decreased cellular proliferation and p53 dependence, and exhibit the hallmarks of immunogenic cell death, suggesting that TTFields treatment may induce an antitumor immune response. Clinical trials lead to Food and Drug Administration approval for their treatment of recurrent glioblastoma. Detailed modeling of TTFields within the brain suggests that the location of the tumor may affect treatment efficacy. These observations have a profound impact on the use of TTFields in the clinic, including what co-therapies may be best applied to boost its efficacy.

Keywords: Computer modeling; Dexamethasone; Glioblastoma; Malignant glioma; Septin; Tubulin; Tumor treating fields.

Fig. 1

Tumor treating fields (TTFields) interact with cells during mitosis. The cell cycle can be separated into interphase and mitosis. Interphase is divided into G1, S, and G2, during which cells grow larger by accumulation of biomass through metabolic processes. Mitosis is divided into prometaphase, metaphase, anaphase, and telophase. These different phases are defined and dominated by biomechanical processes that have evolved to ensure the faithful inheritance of the parental genome in each newly formed daughter cell. TTFields affect cells within anaphase. APC/C = anaphase-promoting complex C

Fig. 2

Transducer array placement on the scalp. As generated by the mapping software NovoTAL, two pairs of arrays are positioned orthogonally in an anterior–posterior (A, B), as well as right–left (C, D), arrangement. These two pairs of arrays are connected to an electric field generator, which is, in turn, either connected to a portable battery pack or a power cord that can be inserted directly into an electric outlet (not shown)

Fig. 3

Computer modeling of electric field distribution within the brain. T1-weighed postgadolinium, T2, and magnetization-prepared rapid gradient-echo magnetic resonance images are imported into Simpleware’s ScanIP 7.0 Suite to perform segmentation of various brain structures, including the scalp, skull, dura, cerebrospinal fluid, gray matter, white matter, brainstem, cerebellum, bilateral ventricles, gross tumor volume, and tumor necrotic core. (A) An air-tight volumetric mesh is then generated for finite element analysis using COMSOL Multiphysics. (B) The distribution of electric fields within the brain is inhomogeneous, with the highest fields at the frontal and occipital horns of the lateral ventricles, as well as the medial surface of the glioblastoma