Abstract
Perhaps the most significant recent advance in oncology therapeutics has been the approval of various "molecularly targeted" anti-cancer drugs. Currently, there are a large number of similar drugs in early or late stage development, including antiangiogenic agents. Clinical development of such drugs suffers from several handicaps including determining whether a patients cancer expresses the target and is functionally contributing to cancer growth, monitoring biologic activity, and determining optimal biologic dose. The last problem is related to the low frequency of objective tumor responses (tumor shrinkage) caused by such drugs, or the lack of dose limiting toxicities necessary to define a maximum tolerated dose (MTD), or expression of optimal therapeutic activity at doses below the MTD, when one can be defined. These problems necessitate the development of alternative pharmacodynamic surrogate markers. Here we summarize several such promising markers for monitoring targeted antiangiogenic activity, and establishing optimal therapeutic/biologic dosing. The first is molecular - plasma VEGF - levels of which are rapidly and significantly increased in a dose dependent manner after injection of normal or tumor bearing mice with anti-VEGFR-2 antibodies. The second is a cellular marker, and more generic in nature - circulating VEGF receptor-2 positive cells found in peripheral blood, some of which may be circulating endothelial progenitor cells. Levels of such cells are suppressed in a dose dependent manner which correlate with previously determined optimal biologic/therapeutic anti-tumor activity of various antiangiogenic drugs or treatments. Finally, another promising marker we discuss is soluble VEGFR-2.
Keywords: tumor angiogenesis, antiangiogenic drugs, targeted therapies, vegf, circulating endothelial progenitor cells, metronomic chemotherapy
Current Cancer Drug Targets
Title: Cellular and Molecular Surrogate Markers to Monitor Targeted and Non- Targeted Antiangiogenic Drug Activity and Determine Optimal Biologic Dose
Volume: 5 Issue: 7
Author(s): Yuval Shaked, Guido Bocci, Raquel Munoz, Shan Man, John M.L. Ebos, Daniel J. Hicklin, Francesco Bertolini, Robert D'Amato and Robert S. Kerbel
Affiliation:
Keywords: tumor angiogenesis, antiangiogenic drugs, targeted therapies, vegf, circulating endothelial progenitor cells, metronomic chemotherapy
Abstract: Perhaps the most significant recent advance in oncology therapeutics has been the approval of various "molecularly targeted" anti-cancer drugs. Currently, there are a large number of similar drugs in early or late stage development, including antiangiogenic agents. Clinical development of such drugs suffers from several handicaps including determining whether a patients cancer expresses the target and is functionally contributing to cancer growth, monitoring biologic activity, and determining optimal biologic dose. The last problem is related to the low frequency of objective tumor responses (tumor shrinkage) caused by such drugs, or the lack of dose limiting toxicities necessary to define a maximum tolerated dose (MTD), or expression of optimal therapeutic activity at doses below the MTD, when one can be defined. These problems necessitate the development of alternative pharmacodynamic surrogate markers. Here we summarize several such promising markers for monitoring targeted antiangiogenic activity, and establishing optimal therapeutic/biologic dosing. The first is molecular - plasma VEGF - levels of which are rapidly and significantly increased in a dose dependent manner after injection of normal or tumor bearing mice with anti-VEGFR-2 antibodies. The second is a cellular marker, and more generic in nature - circulating VEGF receptor-2 positive cells found in peripheral blood, some of which may be circulating endothelial progenitor cells. Levels of such cells are suppressed in a dose dependent manner which correlate with previously determined optimal biologic/therapeutic anti-tumor activity of various antiangiogenic drugs or treatments. Finally, another promising marker we discuss is soluble VEGFR-2.
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Cite this article as:
Shaked Yuval, Bocci Guido, Munoz Raquel, Man Shan, Ebos M.L. John, Hicklin J. Daniel, Bertolini Francesco, D'Amato Robert and Kerbel S. Robert, Cellular and Molecular Surrogate Markers to Monitor Targeted and Non- Targeted Antiangiogenic Drug Activity and Determine Optimal Biologic Dose, Current Cancer Drug Targets 2005; 5 (7) . https://dx.doi.org/10.2174/156800905774574020
DOI https://dx.doi.org/10.2174/156800905774574020 |
Print ISSN 1568-0096 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5576 |
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