Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study

Vergote, Ignace; Moos, Roger von; Manso, Luis; Nieuwenhuysen, Els Van; Concin, Nicole; Sessa, Cristiana

doi:10.1016/j.ygyno.2018.07.018

Cited by 48 publications

(50 citation statements)

References 40 publications

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“…By inhibiting mitosis and cytokinesis, TTFields in particular target fast proliferating cells which results in a certain tumor specificity. Not surprisingly, besides glioblastoma, several other tumor entities such as skin, breast, pancreatic, lung, and ovarian cancer have been reported to react on TTFields in vitro [5,6,7,9,10,11,12,13,14], in preclinical in vivo models [5,9,12,13,15,16,17] or in clinical pilot studies [9,18,19,20]. Notably, best, i.e., most effective TTFields frequency and field strength differ between the different tumor entities with a best frequency of 200 kHz for glioblastoma [4,9,21].…”

Section: Introductionmentioning

confidence: 99%

Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells

Neuhaus

Zirjacks

Ganser

et al. 2019

Cancers

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Tumor treating fields (TTFields) represent a novel FDA-approved treatment modality for patients with newly diagnosed or recurrent glioblastoma multiforme. This therapy applies intermediate frequency alternating electric fields with low intensity to the tumor volume by the use of non-invasive transducer electrode arrays. Mechanistically, TTFields have been proposed to impair formation of the mitotic spindle apparatus and cytokinesis. In order to identify further potential molecular targets, here the effects of TTFields on Ca2+-signaling, ion channel activity in the plasma membrane, cell cycle, cell death, and clonogenic survival were tested in two human glioblastoma cell lines in vitro by fura-2 Ca2+ imaging, patch-clamp cell-attached recordings, flow cytometry and pre-plated colony formation assay. In addition, the expression of voltage-gated Ca2+ (Cav) channels was determined by real-time RT-PCR and their significance for the cellular TTFields response defined by knock-down and pharmacological blockade. As a result, TTFields stimulated in a cell line-dependent manner a Cav1.2-mediated Ca2+ entry, G1 or S phase cell cycle arrest, breakdown of the inner mitochondrial membrane potential and DNA degradation, and/or decline of clonogenic survival suggesting a tumoricidal action of TTFields. Moreover, inhibition of Cav1.2 by benidipine aggravated in one glioblastoma line the TTFields effects suggesting that Cav1.2-triggered signaling contributes to cellular TTFields stress response. In conclusion, the present study identified Cav1.2 channels as TTFields target in the plasma membrane and provides the rationale to combine TTFields therapy with Ca2+ antagonists that are already in clinical use.

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Section: Introductionmentioning

confidence: 99%

Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells

Neuhaus

Zirjacks

Ganser

et al. 2019

Cancers

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“…Although data are accumulating to clarify the MoA of TTFields, ongoing research should help elucidate their impact across different cancer types. In fact, positive, early-phase, clinical trial data suggest potential survival benefits in other tumor types, and clinical trials investigating the efficacy and safety of TTFields in combination with other therapies are underway [ 101 – 103 ]. These include trials evaluating combinations with standard of care therapy in lung, gastrointestinal, ovarian, pancreatic, and hepatocellular cancers, as well as brain metastases (Table 3 ).…”

Section: Discussionmentioning

confidence: 99%

Tumor Treating Fields in the Management of Patients with Malignant Gliomas

Ghiaseddin

Shin

Melnick

et al. 2020

Curr. Treat. Options in Oncol.

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This article is part of the Topical Collection on Neuro-oncology Keywords Tumor treating fields I CNS tumors I Malignant glioma I Glioblastoma I Alternating electric fields I Optune® Opinion statement Malignant gliomas remain a challenging cancer to treat due to limitations in both therapeutic and efficacious options. Tumor treating fields (TTFields) have emerged as a novel, locoregional, antineoplastic treatment modality with favorable efficacy and safety being demonstrated in the most aggressive type of malignant gliomas, glioblastoma (GBM). In 2 large randomized, controlled phase 3 trials, the addition of TTFields was associated with increased overall survival when combined with adjuvant temozolomide (TMZ) chemotherapy in patients with newly diagnosed GBM (ndGBM) and comparable overall survival compared with standard chemotherapy in patients with recurrent GBM (rGBM). TTFields target cancer cells by several mechanisms of action (MoA) including suppression of proliferation, migration and invasion, disruption of DNA repair and angiogenesis, antimitotic effects, and induction of apoptosis and immunogenic cell death. Having several MoAs makes TTFields an attractive modality to combine with standard, salvage, and novel treatment regimens (e.g., radiotherapy, chemotherapy, and immunotherapy). Treatment within the field of malignant gliomas is evolving to emphasize combinatorial approaches that work synergistically to improve patient outcomes. Here, we review the current use of TTFields in GBM, discuss MOA and treatment delivery, and consider the potential for its wider adoption in other gliomas.

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“…The INNOVATE was a single arm trial testing the efficacy of TTFields combined with paclitaxel in patients with recurrent ovarian carcinoma. The 6-months and 1-year survival rates were 90 and 61%, respectively (43). The PANOVA study involved forty patients with newly diagnosed, locally advanced, or metastatic pancreatic ductal adenocarcinoma (PDAC).…”

Section: Other Solid Tumorsmentioning

confidence: 99%

Tumor Treating Fields: At the Crossroads Between Physics and Biology for Cancer Treatment

et al. 2020

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Despite extraordinary advances that have been achieved in the last few decades, cancer continues to represent a leading cause of mortality worldwide. Lethal cancer types ultimately become refractory to standard of care approaches; thus, novel effective treatment options are desperately needed. Tumor Treating Fields (TTFields) are an innovative non-invasive regional anti-mitotic treatment modality with minimal systemic toxicity. TTFields are low intensity (1-3 V/cm), intermediate frequency (100-300 kHz) alternating electric fields delivered to cancer cells. In patients, TTFields are applied using FDA-approved transducer arrays, orthogonally positioned on the area surrounding the tumor region, with side effects mostly limited to the skin. The precise molecular mechanism of the anti-tumor effects of TTFields is not well-understood, but preclinical research on TTFields suggests it may act during two phases of mitosis: at metaphase, by disrupting the formation of the mitotic spindle, and at cytokinesis, by dielectrophoretic dislocation of intracellular organelles leading to cell death. This review describes the mechanism of action of TTFields and provides an overview of the most important in vitro studies that investigate the disruptive effects of TTFields in different cancer cells, focusing mainly on anti-mitotic roles. Lastly, we summarize completed and ongoing TTFields clinical trials on a variety of solid tumors.

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Tumor Treating Fields in combination with paclitaxel in recurrent ovarian carcinoma: Results of the INNOVATE pilot study

Abstract: TTFields combined with weekly paclitaxel were safe in platinum-resistant recurrent ovarian cancer and warrants evaluation in a randomized phase 3 trial.

Cited by 48 publications

References 40 publications

Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells

Alternating Electric Fields (TTFields) Activate Cav1.2 Channels in Human Glioblastoma Cells

Tumor Treating Fields in the Management of Patients with Malignant Gliomas

Tumor Treating Fields: At the Crossroads Between Physics and Biology for Cancer Treatment

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