Ang2 inhibitors and Tie2 activators: potential therapeutics in perioperative treatment of early stage cancer

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.