Division of Clinical Medicine, The University of Sheffield, School of Medicine and Population Health, Sheffield, S10 2RX, UK.
Division of Neuroscience, The University of Sheffield, School of Medicine and Population Health, Sheffield, S10 2RX, UK.
Br J Cancer. 2023 Nov;129(11):1829-1840. doi: 10.1038/s41416-023-02454-0. Epub 2023 Sep 30.
High-grade gliomas are primary brain cancers with unacceptably low and persistent survival rates of 10-16 months for WHO grade 4 gliomas over the last 40 years, despite surgical resection and DNA-damaging chemo-radiotherapy. More recently, tumour-treating fields therapy (TTFields) has demonstrated modest survival benefit and been clinically approved in several countries. TTFields is thought to mediate anti-cancer activity by primarily disrupting mitosis. However, recent data suggest that TTFields may also attenuate DNA damage repair and replication fork dynamics, providing a potential platform for therapeutic combinations incorporating standard-of-care treatments and targeted DNA damage response inhibitors (DDRi).
We have used patient-derived, typically resistant, glioma stem-like cells (GSCs) in combination with the previously validated preclinical Inovitro™ TTFields system together with a number of therapeutic DDRi.
We show that TTFields robustly activates PARP- and ATR-mediated DNA repair (including PARylation and CHK1 phosphorylation, respectively), whilst combining TTFields with PARP1 or ATR inhibitor treatment leads to significantly reduced clonogenic survival. The potency of each of these strategies is further enhanced by radiation treatment, leading to increased amounts of DNA damage with profound delay in DNA damage resolution.
To our knowledge, our findings represent the first report of TTFields applied with clinically approved or in-trial DDRi in GSC models and provides a basis for translational studies toward multimodal DDRi/TTFields-based therapeutic strategies for patients with these currently incurable tumours.
高级别神经胶质瘤是原发性脑癌，在过去的 40 年中，尽管进行了手术切除和 DNA 损伤化疗放疗，世界卫生组织（WHO）4 级神经胶质瘤的生存率仍持续保持在 10-16 个月的不可接受水平。最近，肿瘤治疗电场疗法（TTFields）已被证明具有适度的生存获益，并在多个国家获得临床批准。TTFields 被认为主要通过干扰有丝分裂来发挥抗癌活性。然而，最近的数据表明，TTFields 还可能减弱 DNA 损伤修复和复制叉动力学，为包含标准治疗和靶向 DNA 损伤反应抑制剂（DDRi）的治疗组合提供了潜在平台。
我们使用了源自患者的、通常具有耐药性的神经胶质瘤干细胞样细胞（GSCs），结合了先前验证的临床前 Inovitro™ TTFields 系统以及多种治疗性 DDRi。
我们表明 TTFields 可强烈激活 PARP 和 ATR 介导的 DNA 修复（分别包括 PAR 化和 CHK1 磷酸化），而将 TTFields 与 PARP1 或 ATR 抑制剂联合治疗会导致克隆存活显著降低。这些策略中的每一种策略的效力都通过放射治疗进一步增强，导致 DNA 损伤增加，并严重延迟 DNA 损伤修复。
据我们所知，我们的发现代表了在 GSC 模型中首次应用 TTFields 联合临床批准或临床试验中的 DDRi 的报告，并为针对这些目前无法治愈的肿瘤的多模式 DDRi/TTFields 治疗策略的转化研究提供了基础。
