Tumor treating fields (TTFields) delay DNA damage repair following radiation treatment of glioma cells

Abstract

BackgroundTumor Treating Fields (TTFields) are an anti-neoplastic treatment modality delivered via application of alternating electric fields using insulated transducer arrays placed directly on the skin in the region surrounding the tumor. A Phase 3 clinical trial has demonstrated the effectiveness of continuous TTFields application in patients with glioblastoma during maintenance treatment with Temozolomide. The goal of this study was to evaluate the efficacy of combining TTFields with radiation treatment (RT) in glioma cells. We also examined the effect of TTFields transducer arrays on RT distribution in a phantom model and the impact on rat skin toxicity.MethodsThe efficacy of TTFields application after induction of DNA damage by RT or bleomycin was tested in U-118 MG and LN-18 glioma cells. The alkaline comet assay was used to measure repair of DNA lesions. Repair of DNA double strand breaks (DSBs) were assessed by analyzing γH2AX or Rad51 foci. DNA damage and repair signaled by the activation pattern of phospho-ATM (pS1981) and phospho-DNA-PKcs (pS2056) was evaluated by immunoblotting. The absorption of the RT energy by transducer arrays was measured by applying RT through arrays placed on a solid-state phantom. Skin toxicities were tested in rats irradiated daily through the arrays with 2Gy (total dose of 20Gy).ResultsTTFields synergistically enhanced the efficacy of RT in glioma cells. Application of TTFields to irradiated cells impaired repair of irradiation- or chemically-induced DNA damage, possibly by blocking homologous recombination repair. Transducer arrays presence caused a minor reduction in RT intensity at 20 mm and 60 mm below the arrays, but led to a significant increase in RT dosage at the phantom surface jeopardizing the “skin sparing effect”. Nevertheless, transducer arrays placed on the rat skin during RT did not lead to additional skin reactions.ConclusionsAdministration of TTFields after RT increases glioma cells treatment efficacy possibly by inhibition of DNA damage repair. These preclinical results support the application of TTFields therapy immediately after RT as a viable regimen to enhance RT outcome. Phantom measurements and animal models imply that it may be possible to leave the transducer arrays in place during RT without increasing skin toxicities.Electronic supplementary materialThe online version of this article (10.1186/s13014-017-0941-6) contains supplementary material, which is available to authorized users.

Tumor treating fields cause replication stress and interfere with DNA replication fork maintenance: Implications for cancer therapy

“…This downregulation of FA genes was accompanied by slower DNA repair postradiation and a greater number of residual (unrepaired) DNA lesions at 48 hours. This was confirmed by Giladi et al, who also described a synergistic enhancement of efficacy when TTFields was used in combination with ionizing radiation (IR) in glioma cells 16 including the impairment of radiation-or chemically-induced DNA damage repair. However, while monitoring DSB repair kinetics after IR followed immediately by TTFields exposure, it was noted that the number of g-H2AX foci was substantially greater than that of g-H2AX-53BP1 co-localized foci.…”

Concurrent Tumor Treating Fields (TTFields) and Radiation Therapy for Newly Diagnosed Glioblastoma: A Prospective Safety and Feasibility Study

“…When the initiation of TTFields was delayed until the end of RT treatment, the overall treatment efficacy diminished. This suggests that TTFields radiosensitized cancer cells, which may provide a therapeutic advantage in treating RT-resistant glioma cells (16). Exposing cells to TTFields immediately following ionizing radiation resulted in increased chromatid aberrations and a reduced capacity to repair DNA double-strand breaks, suggesting that TTFields induce a state of "BRCAness, " leading to enhanced sensitivity to ionizing radiation, which underscored a rationale for the use of TTFields combined with RT (12).…”

“…In addition, this population included patients with early disease progression; these patients were excluded from the EF-14 study. Preclinical studies demonstrated the rationale for combining TTFields with RT to treat GBM (16,17). In vitro TTFields plus RT has synergistic antimitotic effects, which lead to increased mitotic catastrophe in GBM cells via inhibition of cell survival, regulation of cell cycle, and hindering of DNA repair (17).…”

“…In vitro TTFields plus RT has synergistic antimitotic effects, which lead to increased mitotic catastrophe in GBM cells via inhibition of cell survival, regulation of cell cycle, and hindering of DNA repair (17). In glioma cell cultures, TTFields increase the kill rate of RT, thereby achieving greater RT efficacy by inhibiting or delaying DNA damage repair and promoting cell death (16). When the initiation of TTFields was delayed until the end of RT treatment, the overall treatment efficacy diminished.…”

“…A synergistic effect between TTFields and RT was demonstrated in glioma cell culture, possibly through inhibition of double-stranded DNA damage repair mechanisms, increased mitotic catastrophe, and decreased glioma cell survival (16,17). This preclinical evidence suggests that GBM patients may benefit from the concurrent administration of TTFields with RT and TMZ.…”