Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models

Mumblat, Helena; Martinez-Conde, Antonia; Braten, Ori; Munster, Mijal; Dor-On, Eyal; Schneiderman, Rosa S.; Porat, Yaara; Voloshin, Tali; Davidi, Shiri; Blatt, Roni; Shteingauz, Anna; Tempel-Brami, Catherine; Zeevi, Einav; Lajterer, C.; Shmueli, Y.; Danilov, S.; Haber, Adi; Giladi, Moshe; Weinberg, Uri; Kinzel, Adrian; Palti, Yoram

doi:10.1016/j.lungcan.2021.08.011

Cited by 28 publications

(61 citation statements)

References 43 publications

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“…Throughout the study the rats were housed in individual cages to prevent tangling of the wires connected to the device. TTFields (2.4 V/cm RMS; 150 kHz; Novo-TTF100L device) were applied continuously for 5 days through two pairs of perpendicular arrays placed around the tumor, each pair applying unidirectional TTFields for 1 s intermittently [ 21 , 24 ]. Device usage data were recorded to ensure animals successfully received therapy for ≥18 h/day, as per clinical recommendations for maximizing treatment benefits [ 25 , 26 ].…”

Section: Methodsmentioning

confidence: 99%

“…The electric forces that comprise TTFields have been suggested to cause dielectrophoresis and dipole alignment, which disrupt mitotic spindle formation leading to aberrant mitosis and subsequent cell death in dividing cells [ 14 , 15 , 16 ]. Recently, TTFields have been shown to increase replication stress and impair DNA damage repair (DDR) mechanisms [ 17 , 18 , 19 , 20 , 21 ]. TTFields have also been shown to trigger autophagy in the progeny of cells dividing during TTFields application, in response to aberrant mitosis and genotoxic stress within daughter cells [ 22 , 23 ].…”

Section: Introductionmentioning

confidence: 99%

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Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Davidi¹,

Jacobovitch²,

Shteingauz³

et al. 2022

Cancers

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Hepatocellular carcinoma (HCC), a highly aggressive liver cancer, is a leading cause of cancer-related death. Tumor Treating Fields (TTFields) are electric fields that exert antimitotic effects on cancerous cells. The aims of the current research were to test the efficacy of TTFields in HCC, explore the underlying mechanisms, and investigate the possible combination of TTFields with sorafenib, one of the few front-line treatments for patients with advanced HCC. HepG2 and Huh-7D12 human HCC cell lines were treated with TTFields at various frequencies to determine the optimal frequency eliciting maximal cell count reduction. Clonogenic, apoptotic effects, and autophagy induction were measured. The efficacy of TTFields alone and with concomitant sorafenib was tested in cell cultures and in an orthotopic N1S1 rat model. Tumor volume was examined at the beginning and following 5 days of treatment. At study cessation, tumors were weighed and examined by immunohistochemistry to assess autophagy and apoptosis. TTFields were found in vitro to exert maximal effect at 150 kHz, reducing cell count and colony formation, increasing apoptosis and autophagy, and augmenting the effects of sorafenib. In animals, TTFields concomitant with sorafenib reduced tumor weight and volume fold change, and increased cases of stable disease following treatment versus TTFields or sorafenib alone. While each treatment alone elevated levels of autophagy relative to control, TTFields concomitant with sorafenib induced a significant increase versus control in tumor ER stress and apoptosis levels, demonstrating increased stress under the multimodal treatment. Overall, TTFields treatment demonstrated efficacy and enhanced the effects of sorafenib for the treatment of HCC in vitro and in vivo, via a mechanism involving induction of autophagy.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Davidi¹,

Jacobovitch²,

Shteingauz³

et al. 2022

Cancers

Self Cite

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“…The efficacy of TT Fields for the treatment of unresectable malignant pleural mesothelioma in combination with pemetrexed plus cisplatin or carboplatin was assessed in Phase 2 STELLAR clinical trial (55). Based on the STELLAR study, TT Fields in combination with pemetrexed and platinum-based chemotherapeutics were approved by the FDA and received a CE mark in Europe as firstline therapy for unresectable, locally advanced, or metastatic malignant pleural mesothelioma (56). TT Fields at a frequency of 150 kHz exhibited the highest cytotoxicity to mesothelioma cells, led to an enhanced number of DNA double-strand breaks, and diminished expression of Fanconi Anemia (FA)-BRCA DNA repair pathway proteins.…”

Section: Local Therapiesmentioning

confidence: 99%

“…TT Fields at a frequency of 150 kHz exhibited the highest cytotoxicity to mesothelioma cells, led to an enhanced number of DNA double-strand breaks, and diminished expression of Fanconi Anemia (FA)-BRCA DNA repair pathway proteins. The co-treatment of TT Fields with cisplatin or pemetrexed significantly enhanced treatment efficacy (56,57). Nevertheless, there are a few limitations of the STELLAR study that should be mentioned.…”

Section: Local Therapiesmentioning

confidence: 99%

Novel Insights Into Mesothelioma Therapy: Emerging Avenues and Future Prospects

et al. 2022

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Malignant mesothelioma is a rare and aggressive cancer that develops in the thin layer surrounding the mesothelium and is mainly caused by asbestos exposure. Despite improvements in patient prognosis with conventional cancer treatments, such as surgery, chemotherapy, and radiotherapy, there are still no curative treatment modalities for advanced disease. In recent years, new therapeutic avenues have been explored. Improved understanding of the mechanisms underlying the dynamic tumor interaction with the immune system has led to the development of immunotherapeutic approaches. Numerous recent clinical trials have shown a desire to develop more effective treatments that can be used to fight against the disease. Immune checkpoint inhibitors, oncolytic adenoviruses, and their combination represent a promising strategy that can be used to synergistically overcome immunosuppression in the mesothelioma tumor microenvironment. This review provides a synthesized overview of the current state of knowledge on new therapeutic options for mesothelioma with a focus on the results of clinical trials conducted in the field.

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“…Recently, the application of 150 kHz TTFields to two non-epithelioid MPM cell lines was found to increase the formation of DNA double strand breaks, induce the expression of cell cycle inhibitors, and reduce the levels of Fanconi Anemia-BRCA DNA repair pathway proteins. All these effects can conceivably contribute to the increased activity of cisplatin and pemetrexed observed both in in vitro and in vivo tumor models when administered together with TTFields [ 12 ]. Nevertheless, there are still gaps in our understanding of the antineoplastic mechanisms engaged by TTFields in MPM tumors.…”

Section: Introductionmentioning

confidence: 99%

Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations

et al. 2022

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Although clinical antitumor activity of Tumor Treating Fields (TTFields) has been reported in malignant pleural mesothelioma (MPM) patients, the mechanisms behind the different selectivity displayed by the various MPM histotypes to this physical therapy has not been elucidated yet. Taking advantage of the development of well characterized human MPM cell lines derived from pleural effusion and/or lavages of patients’ thoracic cavity, we investigated the biological effects of TTFields against these cells, representative of epithelioid, biphasic, and sarcomatoid histotypes. Growth inhibition and cell cycle perturbations caused by TTFields were investigated side by side with RNA-Seq analyses at different exposure times to identify pathways involved in cell response to treatment. We observed significant differences of response to TTFields among the cell lines. Cell cycle analysis revealed that the most sensitive cells (epithelioid CD473) were blocked in G2M phase followed by formation of polyploid cells. The least sensitive cells (sarcomatoid CD60) were only slightly affected by TTFields with a general delay in all cell cycle phases. Apoptosis was present in all samples, but while epithelioid cell death was already observed during the first 24 h of treatment, sarcomatoid cells needed longer times before they engaged apoptotic pathways. RNA-Seq experiments demonstrated that TTFields induced a transcriptional response already detectable at early time points (8 h). The number of differentially expressed genes was higher in CD473 than in CD60 cells, involving several pathways, such as those pertinent to cell cycle checkpoints, DNA repair, and histone modifications. Our data provide further support to the notion that the antitumor effects of TTFields are not simply related to a non-specific reaction to a physical stimulus, but are dependent on the biological background of the cells and the particular sensitivity to TTFields observed in epithelioid MPM cells is associated with a higher transcriptional activity than that observed in sarcomatoid models.

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Tumor Treating Fields (TTFields) downregulate the Fanconi Anemia-BRCA pathway and increase the efficacy of chemotherapy in malignant pleural mesothelioma preclinical models

Cited by 28 publications

References 43 publications

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Tumor Treating Fields (TTFields) Concomitant with Sorafenib Inhibit Hepatocellular Carcinoma In Vitro and In Vivo

Novel Insights Into Mesothelioma Therapy: Emerging Avenues and Future Prospects

Tumor treating fields affect mesothelioma cell proliferation by exerting histotype-dependent cell cycle checkpoint activations and transcriptional modulations

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