Gupta Shilpa, Gill David, Pal Sumanta K, Agarwal Neeraj
H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA,
Curr Oncol Rep. 2015 Apr;17(4):14. doi: 10.1007/s11912-015-0441-5.
Development of anti-angiogenic therapy including the vascular endothelial growth factor (VEGF) antibodies and VEGF-tyrosine kinase receptors has been a major landmark in cancer therapy leading improvement in survival in several cancers. While anti-angiogenic therapy is effective in some settings, resistance often develops owing to evasive, alternative pathways. Novel targets for anti-angiogenic therapy are urgently required to provide treatment alternatives in patients whose tumors are unresponsive to approved anti-angiogenic agents; one such pathway is the bone morphogenetic proteins (BMP 9 and BMP 10) that activate the type I activin receptor-like kinase-1 (ALK1), which has been implicated in the development of functional vasculature. Dalantercept (ACE-041) is a novel anti-angiogenic agent, which is a soluble form of ALK1, and acts as a ligand trap for BMP 9 and BMP 10, inhibiting their interaction with ALK1, which further disrupts the process of vascular development. This review will discuss the preclinical and clinical development of dalantercept as a novel anti-angiogenic therapy in treating a variety of cancers and its distinct safety profile compared to other anti-VEGF agents. We will also discuss the ongoing and completed studies of dalantercept, including combination studies with other VEGF-directed therapies.
包括血管内皮生长因子（VEGF）抗体和VEGF酪氨酸激酶受体在内的抗血管生成疗法的发展是癌症治疗中的一个重要里程碑，使多种癌症的生存率得到了提高。虽然抗血管生成疗法在某些情况下有效，但由于存在逃避性的替代途径，常常会产生耐药性。迫切需要新的抗血管生成治疗靶点，为那些肿瘤对已批准的抗血管生成药物无反应的患者提供治疗选择；其中一条途径是骨形态发生蛋白（BMP 9和BMP 10），它们可激活I型激活素受体样激酶-1（ALK1），而ALK1与功能性脉管系统的发育有关。达兰西普（ACE-041）是一种新型抗血管生成药物，它是ALK1的可溶性形式，可作为BMP 9和BMP 10的配体陷阱，抑制它们与ALK1的相互作用，进而破坏血管发育过程。本文将讨论达兰西普作为一种新型抗血管生成疗法在治疗多种癌症方面的临床前和临床研究进展，以及与其他抗VEGF药物相比其独特的安全性。我们还将讨论达兰西普正在进行和已完成的研究，包括与其他VEGF靶向疗法的联合研究。
