Bhatt Rupal S, Atkins Michael B
Authors' Affiliations: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts and Departments of Oncology and Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia
Authors' Affiliations: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts and Departments of Oncology and Medicine, Georgetown-Lombardi Comprehensive Cancer Center, Washington, District of Columbia.
Clin Cancer Res. 2014 Jun 1;20(11):2838-45. doi: 10.1158/1078-0432.CCR-13-2788. Epub 2014 Apr 8.
The vascular endothelial growth factor (VEGF) pathway is critical for tumor angiogenesis. However, VEGF pathway inhibition has been limited by intrinsic and acquired resistance. Simultaneously targeting multiple steps involved in tumor angiogenesis is a potential means of overcoming this resistance. Activin like kinase 1 (ALK1) and endoglin (ENG) have effects on angiogenesis that are distinct from those of VEGF. Whereas VEGF is important for vessel initiation, ALK1 and endoglin are involved in vessel network formation. Thus, ALK1 and endoglin pathway inhibitors are attractive partners for VEGF-based combination antiangiogenic therapy. Genetic evidence supports a role for this receptor family and its ligands, bone morphogenetic proteins (BMP) 9 and 10, in vascular development. Patients with genetic alterations in ALK1 or endoglin develop hereditary hemorrhagic telangiectasia, a disorder characterized by abnormal vessel development. There are several inhibitors of the ALK1 pathway advancing in clinical development for treatment of various tumor types, including renal cell and ovarian carcinomas. Targeting of alternate angiogenic pathways, particularly in combination with VEGF pathway blockade, holds the promise of optimally inhibiting angiogenically driven tumor progression. Clin Cancer Res; 20(11); 2838-45. ©2014 AACR.
血管内皮生长因子（VEGF）通路对肿瘤血管生成至关重要。然而，VEGF通路抑制一直受到内在和获得性耐药的限制。同时靶向肿瘤血管生成涉及的多个步骤是克服这种耐药性的一种潜在手段。激活素样激酶1（ALK1）和内皮糖蛋白（ENG）对血管生成的作用不同于VEGF。VEGF对血管起始很重要，而ALK1和内皮糖蛋白参与血管网络形成。因此，ALK1和内皮糖蛋白通路抑制剂是基于VEGF的联合抗血管生成治疗的有吸引力的伙伴。遗传学证据支持该受体家族及其配体骨形态发生蛋白（BMP）9和10在血管发育中的作用。ALK1或内皮糖蛋白发生基因改变的患者会患上遗传性出血性毛细血管扩张症，这是一种以血管发育异常为特征的疾病。有几种ALK1通路抑制剂正在临床开发中用于治疗各种肿瘤类型，包括肾细胞癌和卵巢癌。靶向替代血管生成通路，特别是与VEGF通路阻断联合使用，有望最佳地抑制血管生成驱动的肿瘤进展。《临床癌症研究》；20（11）；2838 - 45。©2014美国癌症研究协会。
