调节或跳过:利用适应性疗法降低卵巢癌中 PARP 抑制剂维持疗法的等级。

Cell systems Pub Date : 2024-06-19 Epub Date: 2024-05-20 DOI:10.1016/j.cels.2024.04.003
Maximilian A R Strobl, Alexandra L Martin, Jeffrey West, Jill Gallaher, Mark Robertson-Tessi, Robert Gatenby, Robert Wenham, Philip K Maini, Mehdi Damaghi, Alexander R A Anderson
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引用次数: 0

摘要

多腺苷核糖聚合酶抑制剂(PARPi)对卵巢癌的维持治疗面临着毒性和新出现的耐药性这两个重要挑战。我们建议采用自适应疗法,即根据肿瘤动态动态减少治疗次数,从而缓解这两个问题。利用体外延时显微镜和逐步模型选择,我们校准并验证了一个微分方程数学模型,并利用该模型测试了不同的合理适应性治疗方案。我们的模型表明,由于细胞杀伤延迟和剂量-反应关系减弱,调整剂量比跳过治疗更能有效减少药物用量,同时保持疗效。体内试点实验证实了这一结论。虽然我们的重点是减轻毒性,但减少用药也可能延迟耐药性的产生。这项研究加深了我们对 PARPi 治疗计划的理解,并说明了为新的治疗环境开发适应性疗法的第一步。补充信息中包含了本文透明的同行评审过程记录。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy.

To modulate or to skip: De-escalating PARP inhibitor maintenance therapy in ovarian cancer using adaptive therapy.

Toxicity and emerging drug resistance pose important challenges in poly-adenosine ribose polymerase inhibitor (PARPi) maintenance therapy of ovarian cancer. We propose that adaptive therapy, which dynamically reduces treatment based on the tumor dynamics, might alleviate both issues. Utilizing in vitro time-lapse microscopy and stepwise model selection, we calibrate and validate a differential equation mathematical model, which we leverage to test different plausible adaptive treatment schedules. Our model indicates that adjusting the dosage, rather than skipping treatments, is more effective at reducing drug use while maintaining efficacy due to a delay in cell kill and a diminishing dose-response relationship. In vivo pilot experiments confirm this conclusion. Although our focus is toxicity mitigation, reducing drug use may also delay resistance. This study enhances our understanding of PARPi treatment scheduling and illustrates the first steps in developing adaptive therapies for new treatment settings. A record of this paper's transparent peer review process is included in the supplemental information.

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