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Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations?

Nature Clinical Practice Oncology volume 5, pages 378–391 (2008)Cite this article

Abstract

Since 2004, four antiangiogenic drugs have been approved for clinical use in patients with advanced solid cancers, on the basis of their capacity to improve survival in phase III clinical studies. These achievements validated the concept introduced by Judah Folkman that the inhibition of tumor angiogenesis could control tumor growth. It has been suggested that biomarkers of angiogenesis would greatly facilitate the clinical development of antiangiogenic therapies. For these four drugs, the pharmacodynamic effects observed in early clinical studies were important to corroborate activities, but were not essential for the continuation of clinical development and approval. Furthermore, no validated biomarkers of angiogenesis or antiangiogenesis are available for routine clinical use. Thus, the quest for biomarkers of angiogenesis and their successful use in the development of antiangiogenic therapies are challenges in clinical oncology and translational cancer research. We review critical points resulting from the successful clinical trials, review current biomarkers, and discuss their potential impact on improving the clinical use of available antiangiogenic drugs and the development of new ones.

Key Points

  • Four antiangiogenic drugs, bevacizumab, sorafenib, sunitinib and temsirolimus, have been approved for clinical use on the basis of results from randomized phase III clinical trials without significant contributions from biomarkers

  • No validated biomarkers of angiogenesis or antiangiogeneic activity are available for routine clinical use

  • Biomarkers of angiogenesis might be useful for monitoring angiogenesis, assessing drug activity and distinguishing between active and inactive drugs, predicting clinical outcome and response to therapy, defining the optimum biological dose, facilitating development of combination therapies, and rapidly identifying resistance to treatment

  • Biomarkers under consideration for clinical use include circulating cells, proteins (e.g. angiogenic factors, angiogenesis-associated molecules; protein expression profiles), nucleic acids (e.g. gene-expression patterns) and functional parameters (e.g. tumor perfusion, metabolism)

  • The association of laboratory investigations with clinical trials will be instrumental for the validation of biomarkers of angiogenesis and for improving the design, monitoring and evaluation of antiangiogenic treatments

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Figure 1: Dynamic contrast-enhanced MRI and dynamic contrast-enhanced CT of a hypervascular tumor.
Figure 2: Measurement of perfusion index in a hepatocellular carcinoma by contrast-enhanced ultrasound-based imaging.
Figure 3: Rationale for the use of biomarkers in the development of antiangiogenic therapies.

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Acknowledgements

We thank Drs F Bosman, A Mariotti, M Arditi and R Meuli for helpful comments and discussions, Dr JY Mewly for providing radiological images and R Driscoll for proofreading the manuscript. We apologize to those colleagues whose work could not be cited owing to space limitations. Our research activities are supported by grants from the Swiss National Science Foundation (SNF), Oncosuisse, the National Center for Competence in Research (NCCR, molecular Oncology, a research instrument of the SNF), the Medic Foundation and the Southern European New Drugs Organization (SENDO) Foundation. Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Authors and Affiliations

  1. C Sessa is a Medical and Gynecological Oncologist at the Istituto Oncologico della Svizzera Italiana, Bellinzona,

    Cristiana Sessa

  2. A Guibal is a Radiologist at the Department of Radiology, Centre Hospitalier Universitaire Vaudois, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland,

    Aymeric Guibal

  3. G Del Conte is a Resident Medical Oncologist in the Division of Medical Oncology A, National Cancer Institute, Milan, Italy,

    Gianluca Del Conte

  4. C Rüegg is Head of the Division of Experimental Oncology at the Centre Pluridisciplinaire d'Oncologie, Faculty of Biology and Medicine, University of Lausanne, Lausanne and NCCR Molecular Oncology, Epalinges, Switzerland.,

    Curzio Rüegg

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Sessa, C., Guibal, A., Del Conte, G. et al. Biomarkers of angiogenesis for the development of antiangiogenic therapies in oncology: tools or decorations?. Nat Rev Clin Oncol 5, 378–391 (2008). https://doi.org/10.1038/ncponc1150

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