PDF(Pubmed)
Abstract：
Endothelial Notch signaling is critical for tumor angiogenesis. Notch1 blockade can interfere with tumor vessel function but causes tissue hypoxia and gastrointestinal toxicity. Notch4 is primarily expressed in endothelial cells, where it may promote angiogenesis; however, effective therapeutic targeting of Notch4 has not been successful. We developed highly specific Notch4-blocking antibodies, 6-3-A6 and humanized E7011, allowing therapeutic targeting of Notch4 to be assessed in tumor models. Notch4 was expressed in tumor endothelial cells in multiple cancer models, and endothelial expression was associated with response to E7011/6-3-A6. Anti-Notch4 treatment significantly delayed tumor growth in mouse models of breast, skin, and lung cancers. Enhanced tumor inhibition occurred when anti-Notch4 treatment was used in combination with chemotherapeutics. Endothelial transcriptomic analysis of murine breast tumors treated with 6-3-A6 identified significant changes in pathways of vascular function but caused only modest change in canonical Notch signaling. Analysis of early and late treatment timepoints revealed significant differences in vessel area and perfusion in response to anti-Notch4 treatment. We conclude that targeting Notch4 improves tumor growth control through endothelial intrinsic mechanisms.
UNASSIGNED: A first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area.
UNASSIGNED: A first-in-class anti-Notch4 agent, E7011, demonstrates strong antitumor effects in murine tumor models including breast carcinoma. Endothelial Notch4 blockade reduces perfusion and vessel area.
摘要：
内皮Notch信号传导对于肿瘤血管生成至关重要。Notch1阻断可以干扰肿瘤血管功能，但会引起组织缺氧和胃肠道毒性。Notch4主要在内皮细胞中表达,它可能促进血管生成；然而，Notch4的有效治疗靶向尚未成功。我们开发了高度特异性的Notch4阻断抗体，6-3-A6和人源化E7011,允许在肿瘤模型中评估Notch4的治疗靶向。Notch4在多种肿瘤模型的肿瘤内皮细胞上表达,内皮表达与E7011/6-3-A6反应相关。抗Notch4治疗显著延缓小鼠乳腺模型的肿瘤生长,皮肤,还有肺癌.当抗Notch4治疗与化疗剂组合使用时,发生增强的肿瘤抑制。用6-3-A6处理的鼠乳腺肿瘤的内皮转录组学分析鉴定了血管功能途径的显著变化,但仅引起典型Notch信号传导的适度变化。对早期和晚期治疗时间点的分析显示，响应抗Notch4治疗的血管面积和灌注存在显着差异。我们得出结论，靶向Notch4通过内皮内在机制改善了肿瘤生长控制。
