Angiogenesis inhibitors as therapeutic agents in cancer: Challenges and future directions

Abstract

Angiogenesis has become an attractive target for cancer therapy since the US Food and Drug Administration (FDA) approved the first angiogenesis inhibitor (bevacizumab) for the treatment of metastatic colorectal cancer in 2004. In following years, a large number of angiogenesis inhibitors have been discovered and developed, ranging from monoclonal antibodies, endogenous peptides, to small organic molecules and microRNAs. Many of them are now entering the clinical trial, or achieving approval for clinical use. However, major limitations have been observed about angiogenesis inhibitors by continued clinical investigations, such as resistance, enhancing tumor hypoxia and reducing delivery of chemotherapeutic agents, which might be the main reason for poor improvement in overall survival after angiogenesis inhibitor administration in clinic. Therefore, optimal anti-angiogenic therapy strategies become critical. The present review summarizes recent researches in angiogenesis inhibitors, and proposes a perspective on future directions in this field.

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.