Objectives

Tumor Treating Fields (TTFields) are low intensity, intermediate frequency, alternating electric fields with anti-mitotic effects on cancerous cells. TTFields concomitant with pemetrexed and a platinum agent are approved in the US and EU as first line therapy for unresectable, locally advanced or metastatic malignant pleural mesothelioma (MPM). The goal of the current study was to characterize the mechanism of action of TTFields in MPM cell lines and animal models.

Methods

Human MPM cell lines MSTO-211H and NCI-H2052 were treated with TTFields to determine the frequency that elicits maximal cytotoxicity. The effect of TTFields on DNA damage and repair, and the cytotoxic effect of TTFields in combination with cisplatin and/or pemetrexed were examined. Efficacy of TTFields concomitant with cisplatin and pemetrexed was evaluated in orthotopic IL-45 and subcutaneous RN5 murine models.

Results

TTFields at a frequency of 150 kHz demonstrated the highest cytotoxicity to MPM cells. Application of 150 kHz TTFields resulted in increased formation of DNA double strand breaks, elevated expression of DNA damage induced cell cycle arrest proteins, and reduced expression of Fanconi Anemia (FA)-BRCA DNA repair pathway proteins. Co-treatment of TTFields with cisplatin or pemetrexed significantly increased treatment efficacy versus each modality alone, with additivity and synergy exhibited by the TTFields-pemetrexed and TTFields-cisplatin combinations, respectively. In animal models, tumor volume was significantly lower for the TTFields-cisplatin-pemetrexed combination compared to control, accompanied by increased DNA damage within the tumor.

Conclusion

This research demonstrated that the efficacy of TTFields for the treatment of MPM is associated with reduced expression of FA-BRCA pathway proteins and increased DNA damage. This mechanism of action is consistent with the observed synergism for TTFields-cisplatin vs additivity for TTFields-pemetrexed, as cisplatin-induced DNA damage is repaired via the FA-BRCA pathway.

中文翻译：

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肿瘤治疗场 (TTFields) 下调 Fanconi Anemia-BRCA 通路并提高化疗在恶性胸膜间皮瘤临床前模型中的疗效

目标

肿瘤治疗场 (TTFields) 是低强度、中频、交变电场，对癌细胞具有抗有丝分裂作用。TTFields 与培美曲塞和铂类药物联合使用在美国和欧盟被批准作为不可​​切除、局部晚期或转移性恶性胸膜间皮瘤 (MPM) 的一线疗法。当前研究的目标是表征 TTFields 在 MPM 细胞系和动物模型中的作用机制。

方法

人 MPM 细胞系 MSTO-211H 和 NCI-H2052 用 TTFields 处理以确定引起最大细胞毒性的频率。检查了 TTFields 对 DNA 损伤和修复的影响，以及 TTFields 与顺铂和/或培美曲塞联合的细胞毒性作用。在原位 IL-45 和皮下 RN5 鼠模型中评估了 TTFields 与顺铂和培美曲塞联合使用的功效。

结果

频率为 150 kHz 的 TTFields 显示出对 MPM 细胞的最高细胞毒性。150 kHz TTFields 的应用导致 DNA 双链断裂的形成增加、DNA 损伤诱导的细胞周期停滞蛋白的表达升高，以及范可尼贫血 (FA)-BRCA DNA 修复途径蛋白的表达降低。TTFields 与顺铂或培美曲塞的共同治疗与单独使用每种方式相比显着提高了治疗效果，TTFields-培美曲塞和 TTFields-顺铂组合分别表现出相加性和协同作用。在动物模型中，与对照相比，TTFields-顺铂-培美曲塞组合的肿瘤体积显着降低，伴随着肿瘤内 DNA 损伤的增加。

结论

这项研究表明，TTFields 治疗 MPM 的功效与 FA-BRCA 通路蛋白的表达减少和 DNA 损伤增加有关。这种作用机制与观察到的 TTFields-顺铂与 TTFields-培美曲塞的可加性的协同作用一致，因为顺铂诱导的 DNA 损伤是通过 FA-BRCA 途径修复的。