September 2014 Edition Vol.11, Issue 9

Evolution of Angiogenesis Biomarkers: What the Future Holds

Evolution of Angiogenesis Biomarkers:
What the Future Holds (continued)

Soluble Growth Factor Receptors:

In addition to being embedded in the plasma membranes of cells, growth factor receptors are also present in circulation. The circulating levels of these soluble receptors have been proposed to serve as biomarkers for anti-angiogenic treatment. Significantly attenuated soluble VEGFR-2 (sVEGFR-2) levels in plasma have been reported in response to anti-VEGFR tyrosine kinase inhibitors in several studies.6

In a neoadjuvant study of rectal cancers treated with bevacizumab and chemoradiation, Duda et al. found that low pre-treatment levels of circulating sVEGFR-1, an endogenous blocker of VEGF, correlated both with response to treatment and with treatment toxicity. They suggest that sVEGFR1 is potentially a predictive biomarker in this disease.7

Other Molecular Biomarkers:

Apart from VEGF receptors, there are other soluble factors in circulation that may be exploited as biomarkers. The Ang-TIE pathway of angiogenesis includes cytokines that help maintain the endothelial cell lining of blood vessels.8 Angiopoeitin and its receptor, both of which are components of the Ang-TIE pathway, have been identified to be potentially useful.

For example, in a Phase 3 trial of gemcitabine (Gemzar) with bevacizumab or placebo in pancreatic cancer patients, low levels of Ang-2 and the chemokine, SDF1, as well as high levels of VEGF-D correlated with a lack of benefit from bevacizumab treatment.9 These data support the potential application of Ang2, SDF1, and VEGF-D as predictive biomarkers for bevacizumab treatment in pancreatic cancer. Similar data with these and other potential biomarkers have been demonstrated in other cancer types, including renal cancer.10

CECs and CEPCs:

Circulating endothelial cells (CECs) released from the tumor vasculature and circulating endothelial progenitor cells (CEPCs) from the bone marrow have also been investigated as angiogenic biomarkers in preclinical as well as clinical studies.11 Changes in the number of CECs and CEPCs in the peripheral blood of patients undergoing treatment have been evaluated. However, the results have been inconsistent.12

Challenges and Missing Links:

The above-mentioned studies are only a few examples of the existing data suggesting that biomarkers may help to better guide the use of anti-angiogenic drugs and thereby result in greater clinical efficacy. However, these data are collectively inconsistent and thus, insufficient to permit the routine use of any of these biomarkers clinically, particularly for predictive applications.

Another major challenge hindering clinical progress is that the currently approved tyrosine kinase inhibitors (TKIs) that have anti-angiogenic properties target multiple kinases, which are affected in a distinct manner. For instance, sunitinib (Sutent) is capable of inhibiting VEGFR-1, -2, -3, PDGFRA, and PDGFRB. Thus, it is difficult to correlate its effects with the inhibition of a particular target kinase.2 To further complicate this issue, TKIs and other anti-angiogenic agents are generally used in combination with chemotherapy, making it challenging to attribute an effect to a particular agent-biomarker pair.

Additionally, variability in testing may have an impact on data interpretation. These include factors related to2, 12:

  • tissue sampling, which can lead to variable results due to tumor heterogeneity,
  • the type of clinical specimen, e.g. serum, plasma, or tissue,
  • the availability of concurrent biomarker test results and patient outcome data, and
  • the selection of the appropriate endpoints to determine the efficacy of the biomarker as predictive. 

The existing data around angiogenic molecules in different cancer types, coupled with the discovery of novel biomarkers and the strategic design of future validation trials, may help address some of these issues.12  

Leveraging Vascular Normalization and Immune Modulation:

More than a decade ago, the concept of tumor vasculature normalization of angiogenesis emerged13. It was proposed that certain anti-angiogenic agents could temporarily normalize the leaky structure of tumor vessels, thus improving tumor blood flow, oxygenation, and drug delivery of chemotherapeutic agents to the tumor cells. The transient period was referred to as the “normalization window”, in which combined chemotherapy or radiation therapy demonstrated better response in the presence of angiogenesis inhibitors.14

For instance, treatment with vandetanib (Caprelsa) (a VEGFR TKI that promotes vascular normalization) in combination with the chemotherapeutic agent docetaxel significantly improved PFS in advanced non-small cell lung cancer patients compared with docetaxel alone (median PFS was 4 months versus 3.2 months).15 Another study showed that radiation treatment during vascular normalization upon sunitinib treatment leads to a synergistic delay in tumor growth in mice.16

Mechanistically, vascular normalization transiently reduces the vessel diameter and permeability, and thins the abnormally thickened basement membrane. Therefore, it was postulated that the extent of normalization could be predictive of response to anti-angiogenic therapy.14

This hypothesis was strengthened by pre-clinical data showing that VEGFR2 blockade led to increased pericyte recruitment to tumor blood vessels in an orthotopic brain tumor model via upregulation of Ang1. This also led to thinning of the abnormally thickened vascular basement membrane via matrix metalloproteinase (MMP) activation.14 Further clinical research showed that evaluation of vascular normalization indicators one-day post-anti-VEGF therapy with cediranib was predictive of response in patients with recurrent glioblastoma.17

Vascular normalization may also play a critical role in the behavior of the immune environment of tumors. In 2012, Huang et al. demonstrated in a pre-clinical animal model that subclinical doses of an anti-VEGFR2 antibody cause vascular normalization and are capable of reprogramming the immune component of the tumor microenvironment to relieve their immunosuppressive effects. Consequently, the antibody potentiated the anti-tumor action of cancer vaccine therapy.18


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