PO.ET06.02 · 实验与分子治疗
通过联合给予PARG抑制剂扩大PARP抑制剂的治疗窗
Expanding the therapeutic window of PARP inhibitors by co-administering PARG inhibitors
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：
同源重组（HR）缺陷使肿瘤对PARP抑制剂（PARPi）敏感，PARPi是HR缺陷癌症的标准治疗。尽管疗效显著，PARPi的临床应用受到靶点相关毒性尤其是贫血的限制，导致约半数接受治疗的患者需要减量和停药。为解决这些局限并扩大PARPi的治疗窗，我们研究了与选择性PARG抑制剂（PARGi）的联合给药。
方法：
使用细胞存活试验评估强效PARP抑制剂（他拉唑帕利talazoparib、沙鲁帕利saruparib）、较弱效PARP抑制剂（尼拉帕利niraparib、奥拉帕利olaparib、卢卡帕利rucaparib）与选择性PARG抑制剂在HR缺陷细胞系中的相互作用。在接受他拉唑帕利（0.2-0.25 mg/kg）或沙鲁帕利（0.1 mg/kg）单独或与正在临床开发的选择性PARG抑制剂联合治疗的小鼠和大鼠中，采用给药4天/停药2天/给药4天的方案评估骨髓毒性。在治疗后一天测量红细胞计数、血细胞比容和体重。使用DLD1-BRCA2敲除细胞系来源异种移植物（CDX），采用给药3天/停药4天的给药方案，评估单独或与PARG抑制剂联合的抗肿瘤疗效。
结果：
在细胞存活试验中，PARG抑制剂未拮抗强效PARPi在HR缺陷细胞中的细胞毒性。在体内，PARPi单药治疗诱导了贫血、体重减轻和死亡。联合给予PARG抑制剂挽救了贫血、减轻了体重减轻并防止了治疗相关死亡。CDX研究表明，与PARG抑制剂联用时PARPi的肿瘤生长抑制得以维持或增强，从而在不损害安全性的情况下允许更高的PARPi剂量。在大鼠中，PARPi诱导的贫血同样被PARG抑制剂挽救。总体而言，该联合改善了治疗窗，使更高PARPi剂量下的疗效得以增强。
结论：
PARG抑制在不损害HR缺陷肿瘤抗癌疗效的情况下选择性减轻PARPi诱导的毒性，从而扩大治疗窗。该方法使更高PARPi剂量成为可能以改善肿瘤控制，或以更少不良事件（尤其是贫血）实现同等疗效。通过降低PARPi相关毒性，PARG抑制还可能促进联合治疗，值得进一步研究。
查看英文原文 English abstract
Background:
Homologous recombination (HR) deficiency sensitizes tumors to PARP inhibitors (PARPi), which are standard-of-care for HR-deficient cancers. Despite their efficacy, clinical use of PARPi is limited by on-target toxicity, particularly anemia, leading to dose reductions and drug holidays in about half of treated patients. To address these limitations and expand the therapeutic window of PARPi, we investigated co-administration with selective PARG inhibitors (PARGi).
Methods:
Cell survival assays were used to evaluate the interaction between potent PARP inhibitors (talazoparib, saruparib), less potent PARP inhibitors (niraparib, olaparib, rucaparib), and selective PARG inhibitors in HR-deficient cell lines. Bone marrow toxicity was assessed in mice and rats treated with talazoparib (0.2-0.25 mg/kg) or saruparib (0.1 mg/kg), administered alone or in combination with selective PARG inhibitors undergoing clinical development, using a 4-days-on/2-days-off/4-days-on regimen. Red blood cell counts, hematocrit, and body weight were measured one day after treatment. Antitumor efficacy was evaluated in DLD1-BRCA2-knockout cell line-derived xenografts (CDX) using a 3-days-on/4-days-off dosing schedule, administered alone or in combination with PARG inhibitors.
Results:
In cell survival assays, PARG inhibitors did not antagonize the cytotoxicity of potent PARPi in HR-deficient cells. In vivo, PARPi monotherapy induced anemia, weight loss, and mortality. Co-administration of PARG inhibitors rescued anemia, attenuated weight loss, and prevented treatment-related deaths. CDX studies demonstrated that tumor growth inhibition by PARPi was maintained or enhanced in combination with PARG inhibitors, allowing higher PARPi dosing without compromising safety. In rats, anemia induced by PARPi was similarly rescued by a PARG inhibitor. Overall, the combination improved the therapeutic window, enabling enhanced efficacy at higher PARPi doses.
Conclusions:
PARG inhibition selectively mitigates PARPi-induced toxicity without compromising anticancer efficacy in HR-deficient tumors, thereby expanding the therapeutic window. This approach enables higher PARPi dosing for improved tumor control or equivalent efficacy with fewer adverse events, particularly anemia. By reducing PARPi-associated toxicity, PARG inhibition may also facilitate combination therapies, warranting further investigation.
利益披露 Disclosure
G. G. Rossetti,
FoRx Therapeutics Stock Option.
M. Petropoulos, None..
T. Rampias, None.
T. D. Halazonetis,
FoRx Therapeutics Stock.