Mechanisms of resistance to vascular endothelial growth factor blockade

Abstract

Angiogenesis is essential for the growth of primary tumors and for their metastasis. This process is induced by factors, such as vascular endothelial growth factors (VEGFs), that bind to transmembrane VEGF receptors (VEGFRs). VEGF‐A is the primary factor involved with angiogenesis; it binds to both VEGFR‐1 and VEGFR‐2. The inhibition of angiogenesis by obstructing VEGF‐A signaling has been investigated as a method to treat solid tumors, but the development of resistance to this blockade has complicated treatment. The major mechanisms of this resistance to VEGF‐A blockade include signaling by redundant receptors, such as the fibroblast growth factors, angiopoietin‐1, ephrins, and other forms of VEGF. Other major mechanisms of resistance are increased metastasis of hypoxia‐resistant tumor cells, recruitment of cell types capable of promoting VEGF‐independent angiogenesis, and increased circulation of nontumor proangiogenic factors. Additional mechanisms of resistance to VEGF‐A blockade include heterogeneity of responsiveness among tumor cells, use of anti‐VEGF‐A agents at insufficient doses or for insufficient duration, altered sensitivity to anti‐VEGF‐A agents by mutations in endothelial cells or vascular remodeling, maintenance of vascular sleeves that allow for easy regrowth of tumor vasculature upon discontinuation of therapy, vascular cooption, and intussusceptive angiogenesis. An understanding of these mechanisms may lead to the development of targeted therapies that overcome this resistance. Some of these approaches include the combined inhibition of redundant angiogenic pathways, proper patient selection for various therapies based on gene expression profiles, blockade of cellular migration by inhibition of colony‐stimulating factor, or the use of agents to disrupt vascular architecture. Cancer 2012;3455–3467. © 2011 American Cancer Society.

Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties

“…23,24 Ang2 has been described to provide compensatory tumor growth during anti-VEGF therapy. 25,26 Therefore, concurrent blockade of both VEGF and Ang2, as demonstrated by vanucizumab, 15 which is currently in a Phase 2 study (ClinicalTrials.gov NCT02141295) may result in improved anti-angiogenic efficacy not achievable with a single agent. We sought to determine whether the Bs4Ab design can be used to concurrently block VEGF and Ang2.…”

Angiogenetic axis angiopoietins/Tie2 and VEGF in familial breast cancer

“…Binding mainly to VEGF receptor 2, VEGF activates angiogenic signals that lead to the proliferation and survival of endothelial cells. 2 Angiopoietin 1 (Ang-1) is a vascular stabilizing factor that is expressed by vascular mural cells and non-vascular normal and tumor cells, whereas angiopoietin 2 (Ang-2) is primarily produced by endothelial cells during vascular remodeling. Both angiopoietins have the capability to bind to Tie2 receptor with similar affinities, but they act as antagonizing molecules: Ang-1-mediated Tie2 activation results in survival signals for endothelial cells and allows vessel maturation and maintenance of vascular integrity.…”

EphA2 protein expression in metastatic renal cell carcinoma treated with VEGF-inhibitors is predictive of patient survival

“…Recent publications refer to the management of anti-angiogenic therapy and focus on the mechanisms of resistance in particular [1,13] . EphA2/ephrin-A1 signaling is one supposed pathway, which contributes to resistance to VEGF-Inhibitors, and mutual modulating activities on expression/activation were observed [2,4,12] .…”

“…Despite these advancements in therapy the primary and secondary resistances to anti-angiogenic treatment are major problems that could not be overcome to date, and molecular predictive factors that identify responders from non-responders remain to be identified [11] . EphA2/ephrin-A1 and VEGF signaling modulate theexpression/ activation of each other [2,4,12] , and additionally EphA2 signaling is one supposed mechanism, which contributes to resistance to VEGF-Inhibitors [1,13] . These reported associations between EphA2 signaling and the VEGF pathway strongly suggest an influence of EphA2 protein expression on response to VEGF-targeted therapy.…”