Targeting the Angiopoietin-2/Tie-2 axis in conjunction with VEGF signal interference

Abstract

Anti-angiogenic therapies target the tumor vasculature, impairing its development and growth. It was hypothesized over 40 years ago by the late Judah Folkman and Julie Denekamp that depriving a tumor of oxygen and nutrients, by targeting the tumor vasculature, could have therapeutic benefits. Identification of growth factors and signaling pathways important in angiogenesis subsequently led to the development of a series of anti-angiogenic agents that over the past decade have become part of the standard of care in several disease settings. Unfortunately not all patients respond to the currently available anti-angiogenic therapies while others become resistant to these agents following prolonged exposure. Identification of new pathways that may drive angiogenesis led to the development of second-generation anti-angiogenic agents such as those targeting the Ang-2/Tie2 axis. Recently, it has become clear that combination of first and second generation agents targeting the blood vessel network can lead to outcomes superior to those using either agent alone. The present review focuses on the current status of VEGF and Ang-2 targeted agents and the potential utility of using them in combination to impair tumor angiogenesis.

The Angiopoietin—Tie System: Common Signaling Pathways for Angiogenesis, Cancer, and Inflammation

“…Numerous reagents targeting the angiopoietin/Tie pathway have been developed and were tested in preclinical or clinical models [23,24,99,100,[103][104][105][106][107][108]. The new drug regimen appears very successful, particularly in combination treatment with drugs that target the VEGF/ VEGFR signaling pathway [23,24]. The combination of VEGF-and angiopoietintargeting drugs appears to be superior to targeting either pathway alone [23,24,38,[109][110][111][112][113].…”

“…by vessel cooption) and tissue remodeling and has been shown to promote new vessel growth in concert with other growth factors [14,16,22]. Consequently, high Ang2 levels have been identified in the serum of patients with different neoplasias and Ang2 has thus also been implicated as a biomarker for cancer and other pathologies that involve neovessel growth or vessel permeability [5,24]. Numerous studies with genetically engineered tumor cells expressing Ang1 or Ang2 provided evidence that both molecules act as agonists/antagonists to induce or inhibit Tie2 downstream signaling [5,68,69].…”

“…A peptibody targeting Ang1 and Ang2 (Trebananib ® /AMG386) [99,100] is currently being explored in a phase III clinical trial and has met the endpoint of improved progression-free survival [101,102]. Numerous reagents targeting the angiopoietin/Tie pathway have been developed and were tested in preclinical or clinical models [23,24,99,100,[103][104][105][106][107][108]. The new drug regimen appears very successful, particularly in combination treatment with drugs that target the VEGF/ VEGFR signaling pathway [23,24].…”

“…Ang2 emerged as a valuable clinical target as it is solely upregulated under angiogenic conditions, where it is also coexpressed with VEGF [14,16,17]. As such, targeting the angiopoietin/Tie signaling pathway opens new avenues for therapeutic inhibition of tumor growth [22][23][24]. A peptibody targeting Ang1 and Ang2 (Trebananib ® /AMG386) [99,100] is currently being explored in a phase III clinical trial and has met the endpoint of improved progression-free survival [101,102].…”

“…13.2). Due to these novel functions and to the specific expression in angiogenic, but not normal vessels, angiopoietins have evolved as a potential target for therapeutic intervention in combination with other angiogenic factors [21][22][23][24].…”