Evolution of Angiogenesis Biomarkers: What the Future Holds
By Jennifer Levin Carter MD, MPH
Since Dr. Judah Folkman’s discovery of the process of angiogenesis, there has been rapid growth in the understanding of its regulation as well as the targeting of its underlying mechanisms.1 To date, there are 13 agents with anti-angiogenic properties approved for the treatment of cancer in the US (Table 1). Despite this progress, the development of angiogenesis inhibitors has experienced multiple setbacks, and continues to be a challenging area in cancer therapeutics. This problem can be attributed to three major causes:
Short-term efficacy or inconsistent benefit of existing therapies. This lack of efficacy has led to FDA approvals for these agents for narrow indications, thus limiting their commercial and clinical potential.
Reliable predictive biomarkers for identifying patients who are most likely to respond are not currently available.
Many anti-angiogenesis agents are associated with the risk of serious adverse events, including bleeding and severe hypertension.2
In order to overcome these barriers, it is critical to define the appropriate use of anti-angiogenesis inhibitors, in addition to developing new anti-angiogenic drugs with improved toxicity profiles. Finding reliable biomarkers that predict efficacy and/or resistance will be necessary if angiogenesis inhibitors are to find more widespread applicability in the treatment of cancer.
Evidence for the Potential of Biomarkers of Response to
Biomarkers have been traditionally classified into 3 categories:
prognostic—these predict patient outcomes regardless of treatment
predictive—these predict how a patient will respond to a specific treatment, and can be predictive of sensitivity or of resistance
pharmacodynamic—these monitor known signaling pathways downstream of a given drug target, to assess in-tissue on target effects
Angiogenesis biomarkers include the angiogenic growth factors—mainly VEGF and its receptors, soluble growth factor receptors, key players in other angiogenic pathways, as well as circulating endothelial cells (CECs) and their progenitors. Current research is attempting to evaluate the prospective applications of each of these types of biomarkers.
VEGF, VEGF Receptors, and Related Growth Factors:
VEGF, which attracts tumor endothelial cells, has been the most studied and frequently targeted angiogenic growth factor. In some cancer types, VEGF levels were found to be up-regulated in tumors and in circulation in cancer patients undergoing anti-VEGF treatment, and were reported to correlate with improved clinical outcomes. For instance, in the AVADO Phase 3 trial of first-line bevacizumab (Avastin) in combination with docetaxel for HER2-negative metastatic breast cancer, high plasma VEGFA and VEGFR2 levels were associated with greater progression-free survival.3
In contrast, in other cancer types, VEGFR1 levels (as measured in the tumor and in circulation) correlated inversely with bevacizumab treatment outcomes. The AViTA trial in 154 pancreatic cancer patients revealed a single nucleotide polymorphism (SNP) on VEGFR1 that correlated with increased VEGFR1 expression and poor outcome with bevacizumab treatment.4
Furthermore, Niers et al., proposed that the “true” circulating VEGF levels in most cancer patients are low, and that the recorded high levels are, in fact, due to VEGF release from activated platelets.5
Other VEGF family growth factors have also shown changes in expression in cancer patients. Circulating levels of placental growth factor (PlGF) in plasma have been reported by multiple research groups to consistently increase in response to anti-VEGF therapy.6 Thus, PlGF has the potential to serve as a pharmacodynamic biomarker and may provide clues to mechanisms of therapy-resistance.