PO.ET05.03 · 实验与分子治疗
E7386联合lenvatinib在人子宫内膜癌异种移植模型中的抗肿瘤和抗血管生成活性
Antitumor and antiangiogenic activities of E7386 in combination with lenvatinib in human endometrial carcinoma xenograft models
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：E7386是CREB结合蛋白（CBP）与beta-catenin之间蛋白-蛋白相互作用的抑制剂。目前，E7386联合lenvatinib（LEN，一种主要靶向VEGFR和FGFR的多受体酪氨酸激酶抑制剂）用于治疗包括子宫内膜癌（EC）在内的晚期实体瘤的临床研究正在进行中（NCT04008797）。我们此前报道，在临床前肝细胞癌肿瘤模型中，E7386联合LEN比单药显示出更强的抗肿瘤活性和肿瘤微血管减少。在本研究中，我们在多个人EC异种移植模型中研究了E7386加LEN的抗肿瘤和抗血管生成活性。
方法：将人EC细胞系（HEC151、HEC251、JHUEM2和HEC50B）皮下接种到雌性裸鼠中。荷EC异种移植肿瘤的小鼠接受E7386（6.25-50 mg/kg，口服[PO]，每日一次[QD]）和/或LEN（10 mg/kg，PO，QD）治疗7-14天。对福尔马林固定石蜡包埋的肿瘤样本使用抗CD31抗体通过免疫组织化学染色进行肿瘤微血管分析。
结果：在所有检测的EC异种移植模型中，E7386联合LEN显示出比任一单药更强的抗肿瘤活性，且无严重体重下降（体重下降>20%）。值得注意的是，在HEC251和HEC50B模型中，联合治疗观察到肿瘤消退。在E7386剂量为25和50 mg/kg时，各模型中抗肿瘤活性的增强均一致观察到。HEC151模型中的肿瘤微血管分析揭示，LEN单药治疗降低了微血管密度，而联合治疗相比LEN单药显示出更强效的抗血管生成活性。
结论：这些结果提示，E7386与LEN联合相比LEN单药对肿瘤微血管发挥了增强的抗血管生成活性，并在临床前EC异种移植模型中展现出强效抗肿瘤活性。
查看英文原文 English abstract
Background: E7386 is an inhibitor of the protein-protein interaction between CREB-binding protein (CBP) and beta-catenin. Currently, a clinical study of E7386 in combination with lenvatinib (LEN), a multiple receptor tyrosine kinase inhibitor mainly targeting VEGFRs and FGFRs, is ongoing for the treatment of advanced solid tumors including endometrial carcinoma (EC) (NCT04008797). We previously reported that E7386 in combination with LEN showed greater antitumor activity and reduction of tumor microvessels than each agent alone in preclinical hepatocellular carcinoma tumor models. In this study, we investigated the antitumor and antiangiogenic activities of E7386 plus LEN in multiple human EC xenograft models.
Methods: Human EC cell lines (HEC151, HEC251, JHUEM2, and HEC50B) were subcutaneously inoculated into female nude mice. Mice with EC xenograft tumors were treated with E7386 at 6.25-50 mg/kg (orally [PO], once daily [QD]) and/or LEN at 10 mg/kg (PO, QD) for 7-14 days. Tumor microvessel analysis of formalin-fixed and paraffin-embedded tumor samples was performed by immunohistochemistry staining using the anti-CD31 antibody.
Results: E7386 in combination with LEN showed enhanced antitumor activity compared with either monotherapy alone without severe body weight loss (>20% body weight loss) in all EC xenograft models tested. Notably, tumor regression was observed by the combination treatment in HEC251 and HEC50B models. The enhancement of antitumor activity was consistently observed across models with E7386 doses at 25 and 50 mg/kg. Tumor microvessel analysis in the HEC151 model revealed that LEN monotherapy decreased the microvessel density, and the combination treatment showed more potent antiangiogenic activity compared with LEN monotherapy.
Conclusion: These results suggest that the combination of E7386 with LEN exerted enhanced antiangiogenic activity against tumor microvessels compared with LEN-alone, and demonstrated potent antitumor activity in preclinical EC xenograft models.
利益披露 Disclosure
Y. Adachi,
Eisai Co., Ltd. Employment.
Y. Narita,
Eisai Co., Ltd. Employment.
S. Yamaguchi,
Eisai Co., Ltd. Employment.
T. Semba,
Eisai Co., Ltd. Employment.