Trends and Challenges in Tumor Anti-Angiogenic Therapies

Abstract

Excessive abnormal angiogenesis plays a pivotal role in tumor progression and is a hallmark of solid tumors. This process is driven by an imbalance between pro- and anti-angiogenic factors dominated by the tissue hypoxia-triggered overproduction of vascular endothelial growth factor (VEGF). VEGF-mediated signaling has quickly become one of the most promising anti-angiogenic therapeutic targets in oncology. Nevertheless, the clinical efficacy of this approach is severely limited in certain tumor types or shows only transient efficacy in patients. Acquired or intrinsic therapy resistance associated with anti-VEGF monotherapeutic approaches indicates the necessity of a paradigm change when targeting neoangiogenesis in solid tumors. In this context, the elaboration of the conceptual framework of "vessel normalization" might be a promising approach to increase the efficacy of anti-angiogenic therapies and the survival rates of patients. Indeed, the promotion of vessel maturation instead of regressing tumors by vaso-obliteration could result in reduced tumor hypoxia and improved drug delivery. The implementation of such anti-angiogenic strategies, however, faces several pitfalls due to the potential involvement of multiple pro-angiogenic factors and modulatory effects of the innate and adaptive immune system. Thus, effective treatments bypassing relapses associated with anti-VEGF monotherapies or breaking the intrinsic therapy resistance of solid tumors might use combination therapies or agents with a multimodal mode of action. This review enumerates some of the current approaches and possible future directions of treating solid tumors by targeting neovascularization.

Keywords: Aflibercept; Bevacizumab; angiogenesis inhibitors; anti-VEGF therapy; anti-angiogenesis therapy of cancer; evasive resistance; small-molecule multikinase-inhibitors; sprouting angiogenesis; stromal microenviroment; vessel normalization.

Figure 1

Steps of tissue hypoxia-triggered neoangiogenesis and progression of neoplastic lesions. VEGF: vascular endothelial growth factor. The initially avascular tumor cell mass, upon reaching a critical size, cannot ensure its further growth without the trophic support of its own circulation. Hypoxic cells of the tumor mass, via angiogenic factors, initiate the “angiogenic switch” by stimulating nearby endothelial cells of the microvasculature of the host/parental tissue in which they arise. Tumor angiogenesis initiates with a detachment of perivascular cells, the degradation of vessel basal lamina and angiogenic sprouting by the formation of filopodia bearing leading-edge endothelial tip cells from the parental vessels. Newly formed sprouts build anastomoses followed by lumen formation and the recruitment of the pericytic cells necessary for perivascular investment. Angiogenesis will continue as the expansive growth of the tumor mass requires further supply. This process forms a vicious circle that is fueled by the tumor vessel leakiness and the suboptimal tumor perfusion that cannot efficiently relief tissue hypoxia. Recruited inflammatory cells contribute significantly to a hostile microenvironment that boosts further uncontrolled neoangiogenesis and play a role in the evasive resistance of solid tumors. Abbreviations: Treg, regulatory T cell; TAM, tumor-associated macrophage; TEM, Tie-2- expressing monocyte.

Figure 2

The VEGF/VEGFR signaling axis, its contribution to neoangiogenesis and treatment modalities interfering with its activity. Binding of VEGF ligands to their cognate receptors leads to receptor dimerization and autophosphorylation triggering a down-stream intracellular phosphorylation cascade. In principle, tumor anti-angiogenesis can be achieved (1) by prohibiting ligand binding to their cognate TK receptors (VEGFR1-3) receptors/non-tyrosine kinase (NRPs) co-receptors either by the withdrawal of pro-angiogenic ligands of the VEGF family (Aflibercept, Bevacizumab) or by blocking the accessibility of the binding pocket for ligands on a particular receptor (Ramucirumab); (2) by interfering with the kinase activity of VEGFRs (small molecule multikinase inhibitors: receptor tyrosine kinase (RTK)-inhibitors). Anti-VEGF-targeted therapies result in the inhibition of down-stream signaling mechanisms, governing a range of steps involved in neovessel formation and/or inflammatory infiltration. Abbreviations: EC, endothelial cell; MΦ, macrophage; PlGF, placental growth factor; RTK, receptor tyrosine kinase; TK-domain, tyrosine kinase-domain; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.

Figure 3

Alternative angiogenic pathways playing a role in tumor angiogenesis, refractoriness, evasive resistance or relapses in response to anti-VEGF monotherapies and tools available for targeting their effects. Resistance to anti-angiogenic therapy might be mediated by angiogenic factors that trigger a switch from an initially VEGF-dependent state to a VEGF-independent angiogenic process. In order to interfere with these alternative pathways, besides the small molecule multikinase inhibitors (RTK-inhibitors) blocking down-stream signal cascade activation even in the presence of receptor occupancy, several recombinant biological tools have been developed. The range of these tools includes decoys (“ligand traps”) aimed at withdrawing alternative pro-angiogenic factors either alone (fibroblast growth factor (FGF)-Trap) or simultaneously with VEGF-A (VF-Trap), engineered multivalent monoclonals (CrossMabs) or antibody tools raised against RTK receptors blocking the access of ligands to their cognate receptor (onartuzumab). Abbreviations: EC, endothelial cell; PC, pericyte; TC, tumor cell; Ang-2, angiopoietin-2; FGF-2, fibroblast growth factor-2; FGFR, fibroblast growth factor receptor; HGF, hepatocyte growth factor; MET, mesenchymal-epithelial transition proto-oncogene; PDGF, platelet-derived growth factor; PDGFR, platelet-derived growth factor receptor; TIE2, Tyrosine kinase with immunoglobulin-like and EGF-like domains 2; RTK, receptor tyrosine kinase.