A decade after bevacizumab (Avastin) debuted as the first anticancer therapy to target angiogenesis, new strategies to attack this hallmark of cancer continue to be a major research focus, resulting in the development of novel agents and fresh treatment settings for existing drugs.
Earlier this year, the FDA approved ramucirumab (Cyramza) for the treatment of patients with advanced gastric or gastroesophageal junction adenocarcinoma that progresses after prior therapies. Additional expansion in this field has come from new indications for previously approved agents, including bevacizumab, and several novel agents hold particular promise as treatments for gynecologic malignancies and non–small cell lung cancer (NSCLC).
Yet despite these advances, researchers are far from reaching a complete understanding of the intricacies of tumor vasculature, and significant barriers prevent antiangiogenic therapy from reaching its full potential.
Forming New Blood Vessels From Old
In contrast to neovascularization, in which new blood vessels are formed from circulating precursor endothelial cells, angiogenesis is the formation of new blood vessels from preexisting ones. While the former occurs predominantly during early development to establish a primitive vascular network, the latter allows for expansion of this network through branching, remodeling, and maturation.
In adults, a delicate balance between pro- and antiangiogenic signaling pathways is maintained so that angiogenesis is only switched on when required for physiological processes such as wound healing or menstruation.
The central angiogenic signaling pathway is governed by the vascular endothelial growth factor receptor (VEGFR). Three VEGFRs (VEGFR 1, 2, and 3) mediate the effects of their ligands; these ligands comprise a family of secreted growth factors, VEGF A through E, that induce proliferation and migration of endothelial cells, the primary cell type involved in the formation of new blood vessels.
What a Tangled Web It Weaves
In the early 1970s, Judah Folkman, MD, who was posthumously honored with a Giants of Cancer Care Award last year, became the founding father of the field of tumor angiogenesis with the observation that tumors are unable to grow beyond a cluster of cells of 2 mm to 3 mm without establishing their own vascular network. Beyond this size, the cells at the outermost perimeter of the tumor are far from the blood supply and begin to be starved of oxygen and nutrients.
In response to their hypoxic environment and genetic alterations that are common in cancer, it is believed that cancer cells induce an angiogenic switch; the cells of the tumor and its microenvironment begin to secrete angiogenic growth and survival factors that tip the balance toward proangiogenic signaling pathways, such as the VEGFR pathway. The new blood vessels are unlike normal vasculature; they are poorly developed, chaotic, and tortuous, which results in aberrant functions.
Key Angiogenesis Elements and Agents
FLT indicates Fms-like tyrosine kinase; KIT, mast/stem cell growth factor receptor; MAPK, mitogen-activated protein kinase; PDGFR, platelet-derived growth factor receptor; PRKC, protein kinase C; RAF1, proto-oncogene c-RAF; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
Wehland M et al. Biomarkers for anti-angiogenic therapy. Int J Mol Sci. 2013;14(5):9338-9364. http://goo.gl/MdALSj. Adapted with permission.
The establishment of new blood vessels supplies the tumor with oxygen and nutrients, while at the same time providing a potential route for metastasis. In subsequent years, the key role of tumor angiogenesis was cemented when Douglas Hanahan and Robert Weinberg named the process as one of the essential biological capabilities required for the transformation of a normal cell to a cancerous one.
Many Roles for Bevacizumab
Given its critical role in angiogenic signaling, the VEGFR pathway has been a substantial focus for the development of therapies that would target aberrant signaling, prevent the formation of tumor vasculature, and cut off tumor blood supply.
In 2004, the FDA approved bevacizumab, a monoclonal antibody targeting VEGF-A, for the first-line treatment of metastatic colorectal cancer in combination with standard chemotherapy. It is now approved in a number of other tumor types and settings (Table).
Most recently, the FDA approved bevacizumab in combination with paclitaxel plus either cisplatin or topotecan as a treatment for patients with persistent, recurrent, or metastatic cervical cancer, based on the extension of overall survival (OS) in the GOG 240 study. Bevacizumab combined with chemotherapy increased OS to 16.8 months compared with 12.9 months for chemotherapy alone.