Therapeutic Innovation Unit, Amgen Inc., 360 Binney Street, AMA1/7-L-12, Cambridge, MA 02142, USA.
Cancer Lett. 2013 May 28;332(2):156-62. doi: 10.1016/j.canlet.2010.11.001. Epub 2011 Jan 8.
The early observation that Apo2L/TRAIL preferentially triggers apoptosis in tumor cells over normal cells highlighted its potential as a candidate therapeutic in cancer. Since its identification in the mid-1990s, our increased understanding of Apo2L/TRAIL and Apo2L/TRAIL receptor signaling has led to the development of several agonists designed to promote tumor cell apoptosis through death receptor engagement. Recombinant human Apo2L/TRAIL/dulanermin is unique in that it is the only agonist which binds both Apo2L/TRAIL death receptors. In pre-clinical studies dulanermin demonstrates broad spectrum anti-tumor activity and the ability to cooperate with multiple conventional and targeted therapies. Results from early stage clinical trials indicate that dulanermin is well tolerated and shows some evidence of clinical activity. Not all tumors are likely to be equally sensitive to apoptosis induction by Apo2L/TRAIL. Therefore, an increased understanding of the regulation of Apo2L/TRAIL signaling should aid in the identification of molecular signatures that define a patient population likely to respond. In this review, current knowledge and new insights about Apo2L/TRAIL signaling is discussed with the focus on the development of Apo2L/TRAIL as a cancer therapeutic.
早期观察到 Apo2L/TRAIL 优先在肿瘤细胞中而非正常细胞中触发细胞凋亡，这突显了其作为癌症候选治疗药物的潜力。自 20 世纪 90 年代中期被发现以来，我们对 Apo2L/TRAIL 和 Apo2L/TRAIL 受体信号的理解不断加深，导致了几种激动剂的开发，这些激动剂旨在通过死亡受体结合促进肿瘤细胞凋亡。重组人 Apo2L/TRAIL/dulanermin 的独特之处在于它是唯一结合两种 Apo2L/TRAIL 死亡受体的激动剂。在临床前研究中，dulanermin 表现出广谱抗肿瘤活性，并能够与多种常规和靶向治疗相结合。早期临床试验结果表明，dulanermin 具有良好的耐受性，并显示出一些临床活性的证据。并非所有肿瘤都可能对 Apo2L/TRAIL 诱导的细胞凋亡同样敏感。因此，增加对 Apo2L/TRAIL 信号转导的调节的理解应该有助于确定定义可能对治疗有反应的患者群体的分子特征。在这篇综述中，讨论了关于 Apo2L/TRAIL 信号的现有知识和新见解，重点是将 Apo2L/TRAIL 开发为癌症治疗药物。
