The Kerbel Laboratory is at the forefront of a promising new treatment paradigm for the treatment of cancer: antiangiogenic therapy. After decades of research by many groups, the first antiangiogenic drug (Avastin) for the treatment of (colorectal) cancer was recently approved by the United States Food and Drug Administration. This sets the stage for a new era of a fundamentally different approach for the treatment of cancer.

• >  What factors regulate tumor angiogenesis?
• >  What are the best targets for antiangiogenic drugs?
• >  What is the best way to combine these drugs with chemotherapy or other therapeutic modalities?
• >  How can we determine, using cellular, molecular or imaging 'surrogate' markers, the optimum doses for such drugs and monitor antiangiogenic activity?
• >  What are the mechanisms of response and resistance to antiangiogenic drugs?
• >  What are the best preclinical models to test antiangiogenic drugs, especially from the viewpoint of metastatic disease?

The Kerbel Laboratory is studying all of these questions, with the greatest emphasis on metronomic low-dose or antiangiogenic chemotherapy. This refers to the use of relatively non-toxic low doses of conventional, chemotherapeutic drugs, given frequently, with no prolonged interruptions. It is thought chemotherapy administered in this way targets the growing neovasculature of tumors, and is ideal to use in combination with new targeted antiangiogenic drugs such as the humanized anti-VEGF antibody, Avastin.

The metronomic therapy concept, co-pioneered in the Kerbel Laboratory, has sped into clinical trial testing in centres throughout Canada, the United States and Europe. The lab is involved in some of these, mostly those to do with the development and use of new surrogate biomarkers. The approach is an excellent example of translational research; that is, discoveries made in the laboratory that can be moved rapidly into the clinic.

In addition to his research and academic postings, Dr. Kerbel is also on the Scientific Advisory Boards of York Medical (YM) Biosciences (Toronto), Lorus Therapeutics (Toronto), Oxigene (Boston), Compound Therapeutics (Waltham, Mass.), Attenuon LLC (San Diego) and a consultant to ImClone Systems, Inc. (New York), Wyeth-Ayerst, USA (Pearl River, New York), and Taiho Pharmaceuticals (Japan).

Recent Key Publications:

• >  Klement, G., Baruchel,S., Rak, J., Man, S., Clark, C., Hicklin, D., Bohlen, P., and Kerbel, R.S. (2000) Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J. Clin. Invest., 105: R15-R24.
  
  
• >  Viloria-Petit, A., Crombet, T., Jothy, S., Hicklin, D., Bohlen, P., Rak, J., Schlaeppi, J.-M., and Kerbel, R.S. (2001) Acquired resistance to the anti-tumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res. 61: 5090-5101.
  
  
• >  Klement, G., Huang, P., Mayer, B., Green, S., Bohlen, P., Hicklin, D. and Kerbel, R.S. (2002) Differences in therapeutic indexes of combination metronomic chemotherapy and an anti-VEGFR-2 antibody in multidrug resistant human breast cancer xenograft . Clin. Cancer Res., 8: 221-232.
  
  
• >  Yu, J.L., Rak, J.W., Coomber, B.L., Hicklin, D.J., and Kerbel, R.S. (2002) Effect of p53 status on tumor response to antiangiogenic therapy. Science, 295: 1526-1528.
  
  
• >  Tran, J., Master, Z., Yu, J., Rak, J., Dumont, D.J., and Kerbel, R.S. (2002) A role of survivin in chemoresistance of endothelial cells mediated by VEGF. Proc. Nat'l. Acad. Sci., USA, 99: 4349-4354.
  
  
• >  Man, S., Bocci, G., Francia, G., Green, S., Jothy, S., Bergers, G., Hanahan, D., Bohlen, P., Hicklin, D., and Kerbel, R. (2002) Anti-tumor and anti-angiogenic effects in mice of low-dose (metronomic) cyclophosphamide administered continuously through the drinking water. Cancer Res., 62: 2731-2735.
  
  
• >  Bocci, G., Nicolaou, K.C., and Kerbel, R. (2002) Protracted low-dose effects on human endothelial cell proliferation, adhesion and migration in vitro reveals a potential "antiangiogenic window" for chemotherapeutic drugs. Cancer Res., 62: 6938-6943.
  
  
• >  Kerbel, R.S. and Folkman, J. (2002) Clinical translation of angiogenesis inhibitors. Nature Reviews Cancer, 2: 727-739.
  
  
• >  Bocci, G., Francia, G., Man, S., Lawler, J., and Kerbel, R.S. (2003) Thrombospondin-1, a mediator of the antiangiogenic effects of low-dose metronomic chemotherapy. Proc. Nat'l Acad. Sci. ( USA), 100: 12917-12922.
  
  
• >  Viloria-Petit, A., Miguerol, L., Yu, J.L., Gertenstein, M., Sheehan, C., May, L., Henkin, J., Lobe. C., Nagy, A., Kerbel, R.S., and Rak, J. (2003) Contrasting effects of VEGF gene disruption in embryonic stem cell-derived versus oncogene-induced tumors. EMBO J., 22: 4091-4102.
  
  
• >  Kerbel, R.S. and Kamen, B.A. (2004) Antiangiogenic basis of low-dose metronomic chemotherapy. Nature Reviews Cancer, 4: 423-436.
  
  
• >  Shaked, Y., Bertolini, F., Rawn, K., Man, S., Rogers, M.S., Cervi, D., Foutz, T., Voskas, D., Dumont, D.J., Ben-David, Y., Lawler, J., Henkin, J., D’Amato, R.J. and Kerbel, R.S. (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7: 101-111, 2005.