As a key regulator of tumor angiogenesis, the vascular endothelial growth factor (VEGF) signaling pathway has been the focus of efforts to treat cancer for more than a decade. The FDA has approved 10 VEGF-targeting agents since 2004, when bevacizumab (Avastin) became the poster child of antiangiogenic therapy. Bevacizumab now carries indications in six different tumor types.
Early expectations of antitumor activity across all cancer types have been tempered by clinical disappointment in many cases and only modest efficacy in others, hindered in part by a lack of validated biomarkers and the intricacies of the tumor vasculature that these drugs target.
Nonetheless, VEGF signaling continues to present a promising target. Clinical experience and an improved understanding of the nuances of this pathway have yielded a growing armory of VEGF-targeting drugs with novel mechanisms of action and expanded indications (Table)
The origins of tumor angiogenesis can be traced to the seminal observations of physician-scientist Judah Folkman, MD, a Giant of Cancer Care award winner, and his colleagues at Harvard Medical School. Although the concept initially met with skepticism, his theory that tumors need to establish a new vasculature to grow beyond the boundaries of the existing blood vessels has set the stage for decades of research in this field.
VEGF Inhibitors in Ongoing Developmenta
aTrial information from NIH Clinical Trials Registry, www.ClinicalTrials.gov. Some phase III trials are ongoing but not enrolling new participants.
bBevacizumab approvals in mCRC were given for first-line, second-line, and retreatment after progression, respectively.
c Ramucirumab is approved separately for single agent and combination therapy in gastric/GEJ cancers. AML indicates acute myeloid leukemia; CRC, colorectal cancer; DTC, differentiated thyroid carcinoma; GEJ, gastroesophageal junction; GBM, glioblastoma; GIST, gastrointestinal stromal tumors; HCC, hepatocellular carcinoma; MTC, medullary thyroid cancer; NSCLC, non-small cell lung cancer; pNET, pancreatic neuroendocrine tumor; RCC, renal cell carcinoma; STS, soft tissue sarcoma.
Beyond the establishment of the primitive vascular network (vasculogenesis) in embryonic development, new blood vessels are typically shaped from preexisting ones via angiogenesis during physiological processes like wound healing. Normally, angiogenesis is tightly regulated by a delicate balance between pro- and anti-angiogenic signals.
Observing that tumors failed to grow beyond a certain size without the supporting blood vessels to provide oxygen and nutrients, Folkman proposed that cancer cells secreted some kind of angiogenic factor to stimulate vascularization to support their continued growth. Ultimately, numerous angiogenic factors have since been identified. Central among them are VEGFs, a family of secreted growth factors that includes VEGF-A, B, C, D and placental growth factor. They bind to three VEGF receptors (VEGFR-1, 2, and 3) on the surface of endothelial cells, the major cell type involved in the formation of new blood vessels. VEGF-A is the most extensively studied isoform and VEGFR-2 is the principal receptor through which its angiogenic effects are mediated.
VEGF-A stimulation triggers VEGFR-2 phosphorylation and the subsequent recruitment and activation of a number of downstream proteins that trigger a cascade of different signaling pathways involved in endothelial cell proliferation, and migration and vascular permeability. It is thought that the oxygen-poor environment of the tumor stimulates the expression of high levels of VEGF on the surface of tumor cells, as well as on normal cells in the surrounding microenvironment.