Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors
Activin Receptor-like Kinase 1 Ligand Trap Reduces Microvascular Density and Improves Chemotherapy Efficiency to Various Solid Tumors
复制标题
DOI：
10.1158/1078-0432.ccr-15-0743
复制
发表时间：
2016-01-01
影响因子：
11.5
通讯作者：
ten Dijke, Peter
中科院分区：
文献类型：
--
作者：
Hawinkels, Lukas J. A. C.;de Vinuesa, Amaya Garcia;ten Dijke, Peter
目的：抗血管生成治疗，主要针对VEGF，已被应用于癌症患者在过去的十年。然而，经常观察到对抗VEGF疗法的抗性和/或作为单抗剂没有显著益处。因此，需要新的抗血管生成策略。在当前的研究中，我们研究了通过使用ALK 1-Fc配体陷阱干扰骨形态发生蛋白（BMP）9/激活素受体样激酶（ALK）1信号传导途径的治疗效果。我们在黑色素瘤、头颈癌小鼠模型中分析了ALK 1-Fc蛋白作为单药治疗和与化疗联合治疗的体内潜在抗血管生成和抗肿瘤作用，和浸润性小叶乳腺癌。ALK 1-Fc螯合BMP 9和10，并阻止这些配体与内皮细胞ALK 1的结合，后者调节血管生成。然而，这种效果并不伴随着肿瘤体积的减少。肿瘤样本的免疫组织化学分析显示，ALK 1-Fc处理增加了剩余肿瘤血管的周细胞覆盖，并减少了肿瘤内的缺氧。接下来，我们观察到，ALK 1-Fc与顺铂相结合抑制肿瘤生长的乳腺癌和头颈部癌模型比化疗更有效。结论：除了ALK 1-Fc的顺铂治疗是能够增强化疗的细胞毒性作用。我们的结果为在临床环境中探索ALK 1与化疗的联合靶向提供了强有力的理论基础，特别是在正在进行的ALK 1-Fc II期临床试验中。（C）2015年AACR。
Purpose: Antiangiogenic therapy, mostly targeting VEGF, has been applied in cancer patients for the last decade. However, resistance to anti-VEGF therapy and/or no significant benefit as monotherapeutic agent is often observed. Therefore, new antiangiogenic strategies are needed. In the current study, we investigated the therapeutic effect of interfering with the bone morphogenetic protein (BMP)9/activin receptor-like kinase (ALK)1 signaling pathway by using an ALK1-Fc ligand trap.Experimental Design: We analyzed the potential antiangiogenic and antitumor effects of ALK1-Fc protein as monotherapy and in combination with chemotherapy in vivo in mouse models of melanoma, head and neck cancer, and invasive lobular breast carcinomas. ALK1-Fc sequesters BMP9 and 10 and prevents binding of these ligands to endothelial ALK1, which regulates angiogenesis.Results: Treatment of mice with ALK1-Fc strongly decreased the tumors' microvascular density in the three different mouse cancer models. However, this effect was not accompanied by a reduction in tumor volume. Animmunohistochemical analysis of the tumor samples revealed that ALK1-Fc treatment increased the pericyte coverage of the remaining tumor vessels and decreased the hypoxia within the tumor. Next, we observed that combining ALK1-Fc with cisplatin inhibited tumor growth in the breast and head and neck cancer models more efficiently than chemotherapy alone.Conclusions: The addition of ALK1-Fc to the cisplatin treatment was able to enhance the cytotoxic effect of the chemotherapy. Our results provide strong rationale to explore combined targeting of ALK1 with chemotherapy in a clinical setting, especially in the ongoing phase II clinical trials with ALK1-Fc. (C)2015 AACR.