ReviewAngiogenesis inhibitors as therapeutic agents in cancer: Challenges and future directions
Introduction
Solid tumor, as a major type of cancer, is often treated with combination of surgery, chemotherapy, and/or radiation therapy. However, there are numerous challenges in classical chemotherapy, such as resistance and harmful side effects, resulting in the high cancer mortality (Torre et al., 2016). Therefore, new focuses in cancer treatment have been emerging in the past decade, including treatments based on histological subtypes and leveraging the tumor microenvironment (Singh et al., 2016). Another alternative target for tumor therapy as an adjunct to other forms of therapy is the vascular system, which is underscored by the fact that angiogenesis plays a pivotal role in the development, progression, invasion and metastasis of solid tumors (Hanahan and Weinberg, 2011).
Angiogenesis refers to the formation of new blood vessel from pre-existing vessels. It is a complex multistep process, and tightly regulated by a fine balance between inducers and inhibitors that act together to maintain physiological homeostasis (Hanahan and Folkman, 1996). However, proliferating tumor tends to activate angiogenesis by shifting the balance of inducers and inhibitors towards a pro-angiogenic outcome, to fulfill its increased demand of oxygen and nutrients (Carmeliet, 2005). Environmental hypoxia in tumor seems to be a primary factor that turns on ‘angiogenic switch’ by enhancing expression and activation of transcription factor hypoxia-inducible-factor-1 (HIF-1) pathway or HIF-1-independent pathways, and induces the expression of multiple genes contributing to the angiogenic process (Pugh et al., 2003). In 1972, Folkman proposed anti-angiogenesis as a new anticancer strategy for the first time (Folkman, 1972). Seventeen years later, the isolation and cloning of vascular endothelial growth factor A (VEGFA) became a landmark in understanding angiogenic mechanism (Keck et al., 1989), and laid a foundation for the novel field of research into anti-angiogenic treatments for cancer. The active research in this field eventually resulted in US Food and Drug Administration (FDA) approval of bevacizumab (a monoclonal antibody for VEGFA) as the first anti-angiogenic drug for colorectal cancer in 2004 (Hurwitz et al., 2004).
In the past ten years, many potential anti-angiogenic targets were discovered successively, including fibroblast growth factor, matrix metalloproteinase, tumor-associated stromal cell, and cell adhesion molecule (El-Kenawi et al., 2013). Among them, VEGFs and their receptors (VEGF receptor-1, VEGF receptor-2, and VEGF receptor-3), which are characterized by tyrosine kinase activity, play key roles in angiogenesis (Ferrara et al., 2003). Therefore, most of the angiogenesis inhibitors are developed targeting VEGFs or their receptors. To date, a large number of angiogenesis inhibitors have been discovered and developed, ranging from monoclonal antibodies, endogenous angiogenesis peptide inhibitors, to small molecule drugs and microRNAs (Blaschuk, 2012, Huang et al., 2010, Kim et al., 1993, Wang et al., 2013). This review summarizes recent researches in angiogenesis inhibitors, and proposes a perspective on future directions in this field.
Section snippets
Protein inhibitors
Monoclonal antibodies targeting VEGF pathway have been used as a significant addition to cancer therapy. Bevacizumab (Avastin), a humanized monoclonal immunoglobulin G1 antibody, is the most widely studied anti-angiogenic agent across tumor types and settings, which prevents VEGFA from binding to receptors and activating signaling cascades that lead to angiogenesis (Ferrara et al., 2004). Bevacizumab received its first approval by FDA for combination use with standard chemotherapy for
Small molecule inhibitors
In spite of some clinical success of monoclonal antibodies targeting VEGF pathway, EGF pathway, N-Cadherin, and integrin α5β1, exploring small molecule inhibitors is much more popular in pharmacological research.
Receptor tyrosine kinase inhibitors (RTKIs) constitute a big category of small molecule inhibitors which block VEGF-mediated pathway. The small molecule inhibitors of angiogenesis (2-(3,4-Dihydroxyphenyl)-6,7-dimethylquinoxaline-HCl and
Other vascular-targeted approaches
Other angiogenesis inhibitors include immunomodulatory drugs, cox-2 inhibitors, and even microRNAs (Babae et al., 2014, Dormond and Ruegg, 2003, Franks et al., 2004). Apart from angiogenesis inhibitors that compromise the formation of new blood vessels, a second class of specific vascular-targeted agents is vascular disrupting agents (VDAs) targeting the established tumor vasculature and causing an acute and pronounced shutdown of blood vessels resulting in selective tumor necrosis (Hinnen and
Conclusions and future perspective
Despite anti-angiogenic therapy has increased PFS of patients with cancers, the pooled results showed that OS improvement was very limited (Hong et al., 2015, Li et al., 2016). The limitations of applying angiogenesis inhibitors are attributed to: (1) Resistance: Since angiogenesis is a complex process with multistep mechanism, tumor microenvironment plays an important role in mediating resistance to angiogenesis inhibitors. For example, stromal cells upregulated alternative pro-angiogenic
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