Scientists have uncovered critical information that may lead to an urgently needed method for effective monitoring of antiangiogenic cancer therapies. The research, published in the January issue of Cancer Cell, is likely to facilitate development of new antiangiogenic drugs or treatment strategies and allow for accurate determination of the optimal drug doses to use for such therapies.
Antiangiogenic cancer therapy targets the formation of new blood vessels used to support tumor growth. Although many of these agents are currently being tested in clinical trials, no reliable way to monitor the effects of many, if not most, of these therapeutic agents on the inhibition of the complicated process of angiogenesis exists. Dr. Robert S. Kerbel from Women's College Health Sciences Centre in Toronto and colleagues, including Dr. Francesco Bertolini of the European Institute of Oncology in Milan and Dr. Robert D'Amato of Harvard University, examined whether circulating levels of a class of specific blood cells that contribute to the formation of tumor vessels provide any useful information about the effectiveness of angiogenesis inhibitors.
The researchers found that levels of circulating endothelial cells (CECs) and circulating endothelial progenitor cells (CEPs) are quite varied depending on the genetic background of an animal. However, within a particular strain of mice, levels of these cells are influenced by known regulators of blood vessel formation and correlate remarkably with the ability to induce tumor blood vessel growth and the response to antiangiogenic therapy. Importantly, treatment with a drug that interfered with the major signaling receptor for vascular endothelial growth factor (VEGF), a key regulator of blood vessel development, caused a dose-dependent reduction in CEPs. The reduction in CEPs closely reflected the previously established antitumor activity of this VEGF inhibitor, and the optimal decline in CECs and CEPs was reached at the optimal antitumor dose.
The authors conclude that measuring peripheral blood cells can be used as a reliable surrogate for therapeutic inhibition of angiogenesis. "Our results highlight the possibility of a peripheral blood-based cellular assay to both measure and monitor angiogenesis, as well as to monitor antiangiogenic drug activity, the latter of which can be exploited to help establish the optimal biologic dose of such drugs," offers Dr. Kerbel.
Yuval Shaked, Francesco Bertolini, Shan Man, Michael S. Rogers, Dave Cervi, Thomas Foutz, Kimberley Rawn, Daniel Voskas, Daniel J. Dumont, Yaacov Ben-David, Jack Lawler, Jack Henkin, Jim Huber, Daniel J. Hicklin, Robert J. D'Amato, and Robert S. Kerbel: "Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis: Implications for cellular surrogate marker analysis of antiangiogenesis"
The context and implications of this work are discussed in a Preview by Schneider et al.
The other members of the research team include Yuval Shaked, Shan Man, and Kimberley Rawn of Sunnybrook and Women's College Health Sciences Centre in Toronto; Michael S. Rogers of Children's Hospital and Harvard Medical School in Boston; Dave Cervi, Daniel Voskas, Daniel J. Dumont, and Yaacov Ben-David of Sunnybrook and Women's College Health Sciences Centre and University of Toronto in Toronto; Thomas Foutz of European Institute of Oncology in Milan; Jack Lawler of Harvard Medical School and Beth Israel Deaconess Medical Center in Boston; Jack Henkin of Abbott Laboratories in North Chicago; and Jim Huber and Daniel J. Hicklin of ImClone Systems Incorporated in New York.
This work was supported primarily by grants to R.S.K. from the National Cancer Institute of Canada, and also from the National Institutes of Health (NIH) (CA-41233) and the Canadian Institutes of Health Research (CIHR). Support was also received from Associazione Italiana per la Ricerca sul Cancro (AIRC), Instituto Superiore di Sanita (ISS), and the 6th EU framework program "Angiotargeting" to F.B. and from HL68003 and CA92644 (NIH) to J.L. R.S.K. is a Canada Research Chair in Molecular Medicine. Y.S. is a recipient of a postdoctoral fellowship award from the CIHR. D.C. is supported by a studentship award from the CIHR. D.V. is supported by a studentship award from the Heart and Stroke Foundation of Canada (HSFC). D.J.D. is supported by a grant from NIH (NHLBI-R01 HL63224-01A1). Y.B.-D. is supported by grants from NCIC and CIHR. R.J.D. is supported by grants from the NIH (R01-EY12726).
Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D'Amato RJ, Kerbel RS. Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis.
Cancer Cell. 2005 Jan;7(1):101-11.
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