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 second-generation 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.