Integration of Tumor-Treating Fields into the Multidisciplinary Management of Patients with Solid Malignancies

Wang, Yuefeng; Pandey, Manjari; Ballo, Matthew T.

doi:10.1634/theoncologist.2017-0603

Cited by 20 publications

(25 citation statements)

References 48 publications

(90 reference statements)

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“…It is believed to generate a main non-invasive antimitotic effect on the cells by delivering low intensity, intermediate frequency, alternating electric fields, locally targeting the tumor bed. However, the mode of action is not fully understood [ 14 ]. Additionally, the available knowledge as to its therapeutic potential in combination with other treatment regimens, or its potential to attack GSC/EMT is not fully known.…”

Section: Introductionmentioning

confidence: 99%

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide

Vargas-Toscano

Nickel

et al. 2020

Cancers

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Glioblastoma (GBM) is a lethal disease with limited clinical treatment options available. Recently, a new inhibitor targeting the prominent cancer signaling pathway mTOR was discovered (Rapalink-1), but its therapeutic potential on stem cell populations of GBM is unknown. We applied a collection of physiological relevant organoid-like stem cell models of GBM and studied the effect of RL1 exposure on various cellular features as well as on the expression of mTOR signaling targets and stem cell molecules. We also undertook combination treatments with this agent and clinical GBM treatments tumor treating fields (TTFields) and the standard-of-care drug temozolomide, TMZ. Low nanomolar (nM) RL1 treatment significantly reduced cell growth, proliferation, migration, and clonogenic potential of our stem cell models. It acted synergistically to reduce cell growth when applied in combination with TMZ and TTFields. We performed an in silico analysis from the molecular data of diverse patient samples to probe for a relationship between the expression of mTOR genes, and mesenchymal markers in different GBM cohorts. We supported the in silico results with correlative protein data retrieved from tumor specimens. Our study further validates mTOR signaling as a druggable target in GBM and supports RL1, representing a promising therapeutic target in brain oncology.

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Section: Introductionmentioning

confidence: 99%

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide

Vargas-Toscano

Nickel

et al. 2020

Cancers

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“…It has been reported previously that TTFields inhibit tumor cell proliferation, [28][29][30] promote apoptosis, [31][32][33] and increase CD8 + T-cell infiltration in the tumor. 14 To determine whether TEFT suppresses glioblastoma growth by similar mechanisms, we performed immunohistochemical staining on tumor specimens (Figure 6A).…”

Section: Teft-r Promotes Apoptosis and Cd8+ T-cell Infiltration In Vivomentioning

confidence: 99%

Exploring the efficacy of tumor electric field therapy against glioblastoma: An in vivo and in vitro study

Yang

Liu

et al. 2021

CNS Neurosci Ther

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AimsTumor electric fields therapy (TTFields) is emerging as a novel anti‐cancer physiotherapy. Despite recent breakthroughs of TTFields in glioma treatment, the average survival time for glioblastoma patients with TTFields is <2 years, even when used in conjugation with traditional anti‐cancer therapies. To optimize TTFields‐afforded efficacy against glioblastoma, we investigated the cancer cell‐killing effects of various TTFields paradigms using in vitro and in vivo models of glioblastoma.MethodsFor in vitro studies, the U251 glioma cell line or primary cell cultures prepared from 20 glioblastoma patients were treated with the tumor electric field treatment (TEFT) system. Cell number, volume, and proliferation were measured after TEFT at different frequencies (100, 150, 180, 200, or 220 kHz), durations (24, 48, or 72 h), field strengths (1.0, 1.5, or 2.2V/cm), and output modes (fixed or random sequence output). A transwell system was used to evaluate the influence of TEFT on the invasiveness of primary glioblastoma cells. For in vivo studies, the therapeutic effect and safety profiles of random sequence electric field therapy in glioblastoma‐transplanted rats were assessed by calculating tumor size and survival time and evaluating peripheral immunobiological and blood parameters, respectively.ResultsIn the in vitro settings, TEFT was robustly effective in suppressing cell proliferation of both the U251 glioma cell line and primary glioblastoma cell cultures. The anti‐proliferation effects of TEFT were frequency‐ and “dose” (field strength and duration)‐dependent, and contingent on the field sequence output mode, with the random sequence mode (TEFT‐R) being more effective than the fixed sequence mode (TEFT‐F). Genetic tests were performed in 11 of 20 primary glioblastoma cultures, and 6 different genetic traits were identified them. However, TEFT exhibited comparable anti‐proliferation effects in all primary cultures regardless of their genetic traits. TEFT also inhibited the invasiveness of primary glioblastoma cells in transwell experiments. In the in vivo rat model of glioblastoma brain transplantation, treatment with TEFT‐F or TEFT‐R at frequency of 200 kHz and field strength of 2.2V/cm for 14 days significantly reduced tumor volume by 42.63% (TEFT‐F vs. control, p = 0.0002) and 63.60% (TEFT‐R vs. control, p < 0.0001), and prolonged animal survival time by 30.15% (TEFT‐F vs. control, p = 0.0415) and 69.85% (TEFT‐R vs. control, p = 0.0064), respectively. The tumor‐bearing rats appeared to be well tolerable to TEFT therapies, showing only moderate increases in blood levels of creatine and red blood cells. Adverse skin reactions were common for TEFT‐treated rats; however, skin reactions were curable by local treatment.ConclusionTumor electric field treatment at optimal frequency, strength, and output mode markedly inhibits the cell viability, proliferation, and invasiveness of primary glioblastoma cells in vitro independent of different genetic traits of the cells. Moreover, a random sequence electric field output confers considerable anti‐cancer effects against glioblastoma in vivo. Thus, TTFields are a promising physiotherapy for glioblastoma and warrants further investigation.

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“…Several clinical trials are currently being conducted in different anatomic settings (Wang et al 2019), including the advanced stage trials described below.…”

Section: Other Ongoing Clinical Trialsmentioning

confidence: 99%

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

Karanam

Story

2020

International Journal of Radiation Biology

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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.

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Integration of Tumor-Treating Fields into the Multidisciplinary Management of Patients with Solid Malignancies

Cited by 20 publications

References 48 publications

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide

Rapalink-1 Targets Glioblastoma Stem Cells and Acts Synergistically with Tumor Treating Fields to Reduce Resistance against Temozolomide

Exploring the efficacy of tumor electric field therapy against glioblastoma: An in vivo and in vitro study

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

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