合成致死类药物的定量系统药理模型研究与应用进展

Advances in Quantitative Systems Pharmacology Modeling of Synthetic Lethality Drug Research and Development: from Mechanism to Application

摘要

合成致死作为一种精准靶向肿瘤细胞的治疗策略，在癌症治疗中已展现出巨大应用潜力。由于合成致死涉及多条修复通路，其药物靶点研究已从聚腺苷二磷酸核糖聚合酶（poly ADP-ribose polymerase，PARP）扩展至多个新靶点，相关药物已陆续进入关键临床研究阶段。尽管合成致死类药物具有显著的特异性抗癌疗效，但其临床研究仍面临易耐药、血液学毒性等挑战。综述详细总结了合成致死领域多个靶点的作用机制及相关定量系统药理学（quantitative systems pharmacology，QSP）模型研究进展，探讨 QSP 建模通过整合多尺度机制与实验数据，预测合成致死类药物的临床疗效及血液学毒性，从而在临床给药方案设计、剂量优化、联合疗法筛选等方面发挥指导作用，旨在从系统角度精准推动该类药物的临床转化，提升患者临床获益并降低安全性风险。

Abstract

Synthetic lethality has emerged as a promising therapeutic strategy for precision targeting of tumor cells in cancer treatment. As it involves multiple DNA repair pathways, drug target research in this field has expanded from poly ADP-ribose polymerase (PARP) to many novel targets, with related therapies advancing progressively into pivotal clinical trials. Although synthetic lethality drugs can demonstrate significant and specific anticancer efficacy, their clinical development still faces such challenges as acquired resistance and hematological toxicity. To address these limitations, this review comprehensively summarizes the mechanisms of action of multiple targets in the synthetic lethality field and the research progress of quantitative systems pharmacology (QSP) models. QSP modeling, by integrating multi-scale mechanisms and experimental data, enables the prediction of clinical efficacy and hematological toxicity of synthetic lethality drugs. It plays a guiding role in clinical dosing regimen design, dose optimization, and combination therapy screening, thereby advancing the precise clinical translation of such drugs from a systems perspective, aiming to enhance patient clinical benefits and reduce safety risks.

关键词

定量系统药理学 / 合成致死 / 血液学毒性 / 模型引导的药物研发

Key words

quantitative systems pharmacology / synthetic lethality / hematologic toxicity / model-informed drug development

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基金资助

江苏省科技厅创新能力建设计划项目(BM2023004)

中国科协青年人才托举工程(YESS20210160)

南京医科大学引进人才科研启动基金(NMUR20210006)