Perturbing Angiogenic Pathways as a Novel Therapeutic Modality
Key Words: anti-angiogenic therapy; metronomic chemotherapy; acquired drug resistance; vascular endothelial cell growth factor; apoptosis; oncogenes; EGF receptor; cell adhesion and multicellular resistance; clinical trials
Our research is focussed in the area of tumor angiogenesis and antiangiogenic therapy. In this regard, one of the most significant developments in medical oncology over the last five years has been the approval of three different antiangiogenic drugs for the treatment of a number of human cancers, e.g. breast, colorectal, renal, and hepatocellular carcinoma. This includes bevacizumab (Avastin), the humanized anti-VEGF monoclonal antibody which is now undergoing evaluation in almost 400 clinical trials around the world. Despite the successes of antiangiogenic drugs, including bevacizumab, remarkably little is known about how these drugs actually work as anti-cancer agents. The reason for the counterintuitive property of an antiangiogenic drug enhancing the efficacy of chemotherapy is unknown and is a subject of investigation in our laboratory as well as a number of others around the world. In addition, the best way to administer chemotherapy with an antiangiogenic drug remains to be determined. Another major question in the field is how to determine the optimal biologic dose for antiangiogenic drugs and to monitor their activity in vivo.
The Kerbel group is studying the hypothesis that conventional chemotherapy can induce remarkably rapid and marked mobilizations of a proangiogenic cell population from the bone marrow compartment, known as endothelial progenitor cells, which can subsequently home to drug treated tumors and accelerate their recovery from the initial chemotherapy treatment. This reactive host response can be blocked using certain antiangiogenic drugs. The molecular pathways by which these processes occur is under intensive investigation in Dr. Kerbel’s laboratory.
Dr. Kerbel is also pioneering a concept known as ‘metronomic’ chemotherapy (where chemotherapy is given at close regular intervals at low doses with no prolonged drug-free breaks) as an exciting and novel new way to combine chemotherapy with a targeted antiangiogenic drug such as bevacizumab, for the treatment of advanced metastatic disease. We have developed a number of new models of advanced metastatic disease in immune deficient mice involving human tumor cell lines, including breast, ovarian, and hepatocellular carcinoma, as well as malignant melanoma. These studies have evolved in a new research initiative, namely, the development of models of spontaneous brain metastases and their use to study the biology and treatment of such lesions. Finally, our group is at the forefront of studying circulating cellular and molecular surrogate biomarkers in peripheral blood for antiangiogenic drugs and/or metronomic low-dose chemotherapy which can help determine the optimal biologic dose to be used for such drugs/treatments.
- Anthony Mutsaers
Selected Publications:Link to Pubmed Publications
Ebos JM, Lee CR, Christensen JG, Mutsaers AJ, Kerbel RS. Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17069- 74. Epub 2007 Oct 17.
Kerbel RS. Antiangiogenic therapy: a universal chemosensitization strategy for cancer? Science. 2006 May 26;312(5777):1171-5.
Shaked Y, Ciarrocchi A, Franco M, Lee CR, Man S, Cheung AM, Hicklin DJ, Chaplin D, Foster FS, Benezra R, Kerbel RS. Therapy-induced acute recruitment of circulating endothelial progenitor cells to tumors. Science. 2006 Sep 22;313(5794):1785-7.
Klement G, Baruchel S, Rak J, Man S, Clark K, Hicklin DJ, Bohlen P, Kerbel RS. Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity. J Clin Invest. 2000 Apr;105(8):R15-24.
Erratum in: J Clin Invest. 2006Nov;116(11):3084. J Clin Invest. 2006 Oct;116(10):2827.