Anti-angiogenic drugs targeting the VEGF pathway are most effective in advanced metastatic disease settings of certain types of cancers, whereas they have been unsuccessful as adjuvant therapies of micrometastatic disease in numerous phase III trials involving early-stage (resectable) cancers. Newer investigational anti-angiogenic drugs have been designed to inhibit the Angiopoietin (Ang)-Tie pathway. Acting through Tie2 receptors, the Ang1 ligand is a gatekeeper of endothelial quiescence. Ang2 is a dynamically expressed pro-angiogenic destabilizer of endothelium, and its upregulation is associated with poor prognosis in cancer. Besides using Ang2 blockers as inhibitors of tumor angiogenesis, little attention has been paid to their use as stabilizers of blood vessels to suppress tumor cell extravasation and metastasis. In clinical trials, Ang2 blockers have shown limited efficacy in advanced metastatic disease settings. This review summarizes preclinical evidence suggesting the potential utility of Ang2 inhibitors or Tie2 activators as neoadjuvant or adjuvant therapies in the prevention or treatment of early-stage micrometastatic disease. We further discuss the rationale and potential of combining these strategies with immunotherapy, including immune checkpoint targeting antibodies.

中文翻译：

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Ang2抑制剂和Tie2激活剂：早期癌症围手术期治疗的潜在疗法

针对 VEGF 通路的抗血管生成药物在某些类型癌症的晚期转移性疾病中最为有效，但在涉及早期（可切除）癌症的众多 III 期试验中，它们作为微转移性疾病的辅助治疗并不成功。较新的研究性抗血管生成药物旨在抑制血管生成素 (Ang)-Tie 途径。Ang1 配体通过 Tie2 受体发挥作用，是内皮静止的看门人。Ang2是一种动态表达的内皮促血管生成去稳定剂，其上调与癌症的不良预后相关。除了使用Ang2阻滞剂作为肿瘤血管生成的抑制剂外，其作为血管稳定剂抑制肿瘤细胞外渗和转移的用途却很少受到关注。在临床试验中，Ang2 阻滞剂在晚期转移性疾病中的疗效有限。本综述总结了临床前证据，表明 Ang2 抑制剂或 Tie2 激活剂作为新辅助或辅助疗法在预防或治疗早期微转移性疾病中的潜在用途。我们进一步讨论了将这些策略与免疫疗法（包括免疫检查点靶向抗体）相结合的基本原理和潜力。