PO.ET02.08 · 实验与分子治疗
通过脂质体递送和ATR抑制剂联合增强CX-5461在TNBC中的疗效
Enhancing CX-5461 therapy in TNBC through liposomal delivery and ATR inhibitor combination
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：乳腺癌（BC）是女性癌症死亡的第二大原因。三阴性乳腺癌（TNBCs）是一种侵袭性亚型，占病例的15-20%，并在BC死亡率中占据不成比例的高比例。对于转移性TNBC患者，当前的标准治疗方案是化疗；尽管初期有效，但总生存期仍然较差。因此，迫切需要新型治疗策略以改善TNBC的预后。
目的：我们旨在评估新型DNA损伤剂CX-5461（Pidnarulex），该药在具有同源重组缺陷（HRD）的TNBC患者来源异种移植（PDX）模型中展现出令人鼓舞的临床前活性，这些模型来自对标准治疗化疗耐药的转移性患者。CX-5461目前正处于临床试验阶段，并获得了针对具有HRD的乳腺癌和卵巢癌的FDA快速通道认定。为增强疗效并改善生存，我们正在探索脂质体递送以及与ATR抑制剂Berzosertib的合理联合。由于CX-5461在DNA修复缺陷的背景下最为有效，我们聚焦于具有HR或其他DNA修复通路缺陷的模型。
方法：在体外筛选人TNBC细胞系和PDX来源培养物对CX-5461的单药活性。优先选择IC 50 ≤ 5 μM的PDX模型进行体内测试，以确定敏感性（定义为与对照组相比肿瘤体积减少≥50%）。迄今已在体内测试了一个PDX模型（BCM-3887）。CX-5461脂质体采用薄膜水化法并结合基于铜络合的梯度载药法制备。对体外有反应的细胞系和BCM-3887筛选Berzosertib的单药活性。选择对Berzosertib的IC 50 ≤ 10 μM的细胞系和BCM-3887进行体外联合研究，以评估与CX-5461的协同相互作用。
结果：CX-5461展现出强效的体外单药活性。在使用BCM-3887模型的先导体内研究中，观察到强烈的肿瘤生长抑制。制备的脂质体具有良好的物理特性。与Berzosertib的体外联合研究显示出协同作用。
结论：CX-5461是一种针对DNA修复缺陷型TNBC的极具前景的药物，在体外和体内均展现出强效的单药活性。与Berzosertib的初步联合研究揭示了协同潜力。未来的体内研究将评估脂质体递送和联合治疗能否改善TNBC的生存。
查看英文原文 English abstract
Background: Breast cancer (BC) is the second leading cause of cancer death in women. Triple-negative breast cancers (TNBCs), an aggressive subtype, account for 15-20% of cases and disproportionately contribute to BC mortality. For patients with metastatic TNBC, the current standard of care is chemotherapy; although initially effective, overall survival remains poor. Thus, novel therapeutic strategies are urgently needed to improve TNBC outcomes.
Aims: We aim to evaluate the novel DNA-damaging agent CX-5461 (Pidnarulex), which has shown promising preclinical activity in TNBC patient-derived xenograft (PDX) models with homologous recombination deficiency (HRD), derived from metastatic patients resistant to standard-of-care chemotherapy. CX-5461 is currently in clinical trial and holds FDA Fast Track designation for breast and ovarian cancers with HRD. To enhance efficacy and improve survival, we are exploring liposomal delivery and rational combination with the ATR inhibitor, Berzosertib. As CX-5461 is most effective in DNA repair-deficient backgrounds, we focused on models with HR or other DNA repair pathway deficiencies.
Methods: Human TNBC cell lines and PDX-derived cultures were screened in vitro for single-agent CX-5461 activity. PDX models with IC 50 ≤ 5 µM were prioritized for in vivo testing to determine sensitivity (defined as ≥50% tumor volume reduction compared to control). One PDX model (BCM-3887) has been tested in vivo to date. CX-5461 liposomes were prepared using thin-film hydration method with copper complexation-based gradient loading. In vitro responsive cell lines and BCM-3887 were screened for single-agent activity of Berzosertib. Cell lines and BCM-3887 with IC 50 ≤ 10 µM for Berzosertib were selected for in vitro combination studies to evaluate synergistic interactions with CX-5461.
Results: CX-5461 has demonstrated potent in vitro single-agent activity. In a pilot in vivo study using BCM-3887 model, strong tumor growth inhibition was observed. Liposomes were prepared with favorable physical characteristics. In vitro combination studies with Berzosertib showed synergy.
Conclusion: CX-5461 is a promising agent for DNA repair-deficient TNBC, with strong single-agent activity demonstrated in vitro and in vivo. Preliminary combination studies with Berzosertib revealed synergistic potential. Future in vivo studies will evaluate whether liposomal delivery and combination therapy can improve survival in TNBC.
利益披露 Disclosure
H. S. Negash, None..
R. K. Myrick, None..
S. R. da Rocha, None..
J. Harrell, None.