PO.ET02.10 · 实验与分子治疗
在Nectin-4阳性上皮性卵巢癌中的药物重新利用
Drug repurposing in Nectin-4-positive epithelial ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
目的：抗体药物偶联物（ADCs）是用于癌症治疗的有前景的治疗性生物制剂，而米维妥昔单抗索拉伏坦辛（MIRV）是目前唯一获FDA批准用于治疗叶酸受体alpha（FRalpha）阳性铂耐药上皮性卵巢癌（PROC）的ADC。3期EV-302/KEYNOTE-A39试验的结果表明，在转移性尿路上皮癌患者中，Nectin-4定向ADC恩沃单抗维多汀（anti-Nectin-4 ADC）与帕博利珠单抗联合使用比铂类化疗产生更好的治疗结果。本研究旨在探讨将anti-Nectin-4 ADC重新利用为上皮性卵巢癌（EOC）治疗策略的潜力，并探索针对Nectin-4阳性EOC肿瘤的有效联合疗法。
方法：通过多重免疫组化（MIHC）在我们的机构组织队列中验证了EOC中的Nectin-4表达，并在独立的公开数据集中得到证实。使用EOC细胞系中的细胞毒性、凋亡和克隆形成检测评估了anti-Nectin-4 ADC的体外疗效。在患者来源类器官模型和异种移植模型中研究了抗肿瘤活性。
结果：EOC中的Nectin-4表达具有异质性，但与匹配的正常组织相比总体升高。Nectin-4靶向ADC在Nectin-4阳性EOC细胞系中表现出显著的细胞毒性。计算机模拟和体外分析均表明，Nectin-4阳性肿瘤对两种FDA批准的化合物敏感，这可能是由于脂肪酸代谢失调所致。体内研究证实，anti-Nectin-4 ADC单药治疗有效抑制了肿瘤生长，而联合治疗进一步增强了生存结局。
结论：本研究证明了Nectin-4靶向药物在Nectin-4阳性EOC临床前模型中的治疗潜力，支持其向临床转化推进。此外，研究结果表明，重新利用Nectin-4引导的联合疗法可扩大并增强EOC的治疗选择。
查看英文原文 English abstract
Objectives: Antibody-drug conjugates (ADCs) are promising therapeutic biologics for cancer treatment, and Mirvetuximab soravtansine (MIRV) is currently the only FDA-approved ADC for treating folate receptor alpha (FRalpha) positive platinum-resistant epithelial ovarian cancer (PROC). Results from the Phase 3 EV-302/KEYNOTE-A39 trial indicate that the combination of Nectin-4-directed ADC Enfortumab Vedotin-ejfv (anti-Nectin-4 ADC) and pembrolizumab yields better treatment outcomes than platinum-based chemotherapy in patients with metastatic urothelial carcinoma. The study aims to investigate the potential of repurposing anti-Nectin-4 ADC as a therapeutic strategy for epithelial ovarian cancer (EOC), and to explore effective combination therapies targeting Nectin-4-positive EOC tumors.
Methodology: Nectin-4 expression in EOC was validated through multiplex immunohistochemistry (MIHC) in our institutional tissue cohort and corroborated in independent public datasets. In vitro efficacy of anti-Nectin-4 ADC was evaluated using cytotoxicity, apoptosis, and clonogenic assays in EOC cell lines. Anti-tumor activity was investigated in patient-derived organoid models and xenograft models.
Result: Nectin-4 expression in EOC is heterogeneous but generally elevated compared to matched normal tissues. The Nectin-4-targeted ADC demonstrated significant cytotoxicity in Nectin-4-positive EOC cell lines. Both in silico and in vitro analyses revealed that Nectin-4-positive tumors are sensitive to two FDA-approved compounds, potentially due to dysregulated fatty acid metabolism. In vivo studies confirmed that anti-Nectin-4 ADC monotherapy effectively suppressed tumor growth, and combination treatments further enhanced survival outcomes.
Conclusion: This study demonstrates the therapeutic potential of Nectin-4-targeted agents in preclinical models of Nectin-4-positive EOC, supporting their advancement toward clinical translation. Additionally, the findings suggest that repurposing Nectin-4-guided combination therapy could expand and enhance treatment options for EOC.
利益披露 Disclosure
X. Zhong, None..
R. Long, None..
R. Zhang, None..
L. Hung, None..
C. Cui, None..
C. Bao, None..
K. Liu, None..
C. Li, None..
H. Lu, None..
K. Chan, None.