Angiopoietin-2: An Attractive Target for Improved Antiangiogenic Tumor Therapy

Abstract

Anti-VEGF pathway therapies primarily target immature blood vessels in tumors. However, emerging approaches to combine with targeted therapies impacting the later stages of remodeling and vessel maturation are expected to improve clinical efficacy by expanding the target vessel population. The angiopoietin/Tie ligand/ receptor system is a prototypic regulator of vessel remodeling and maturation. Angiopoietin-2 (Ang2) appears to be a particularly attractive therapeutic target. In fact, the experimental proof-of-concept showing improved efficacy when VEGF and Ang2-targeting therapies are combined has been solidly established in preclinical models, and several Ang2-targeting drugs are in clinical trials. However, rational development of these secondgeneration combination therapies is hampered by a limited understanding of the biological complexity that is generated from agonistic and antagonistic Ang/Tie signaling. This review discusses recent mechanistic advances in angiopoietin signaling, particularly in light of the recent study published on REGN910 and summarizes the status quo of Ang2-targeting therapies. In light of the clarified partial agonist function of Ang2, we propose that clarity on the expression profile of the angiopoietin ligands and Tie1 and Tie2 receptors in subsets of cancer vessels and cancer cells will provide clearer hypotheses for more focused rational clinical trials to exploit this seminal pathway and improve current antiangiogenic therapies. Cancer Res; 73(6); 1649-57. Ó2013 AACR.

Angiopoietin-2 Secretion by Endothelial Cell Exosomes

“…Ang2 is thought to be an attractive therapeutic target for the treatment of cancer because combination of VEGF and Ang2-targeting therapies has shown improved efficacy against tumor growth compared with target either VEGF or Ang2 alone (33). The ability of syndecans to regulate the release of Ang2 may provide a novel target for compounds designed to regulate Ang2 levels.…”

Angiogenesis- and Hypoxia-Associated Proteins as Early Indicators of the Outcome in Patients with Metastatic Breast Cancer Given First-Line Bevacizumab-Based Therapy

“…Several proteins are known to exert direct or indirect proangiogenic effects. Among them is the angiopoietins/TIE2 receptor signaling pathway, which is an important regulator in vessel remodeling and maturation (8). Increasing data indicate that angiopoietin 2 (ANG2) can function as a TIE2 agonist, particularly when overexpressed and/or in the absence of ANG1.…”

Heterogeneous perivascular cell coverage affects breast cancer metastasis and response to chemotherapy

“…In patients with breast cancer, Ang2 expression in tumors is associated with lymph node involvement and poor prognosis (27) and serum Ang2 levels present with diagnostic and prognostic potential for human breast cancer (28). Ang2 is implicated in the metastasis of breast cancer (16,24,(29)(30)(31)(32) and emerges as an attractive therapeutic target for breast cancer metastasis (33). However, the complex signaling of Ang2 in the tumor microenvironment and its pleiotropic effect on endothelial cells and perivascular cells may limit the efficacy and response to Ang2-targeted therapies, requiring a deeper understanding of the effect of the Ang2 signaling network on vascular remodeling and cancer cell behavior.…”