Cellular and molecular surrogate markers to monitor targeted and non-targeted antiangiogenic drug activity and determine optimal biologic dose

Yuval Shaked, Guido Bocci, Raquel Munoz, Shan Man, J. M L Ebos, Daniel J. Hicklin, Francesco Bertolini, Robert D'Amato, Robert S. Kerbel

Research output: Contribution to journalArticlepeer-review

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 patient's 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.

Original languageEnglish
Pages (from-to)551-559
Number of pages9
JournalCurrent Cancer Drug Targets
Volume5
Issue number7
DOIs
Publication statusPublished - Nov 2005

Keywords

  • Antiangiogenic drugs
  • Circulating endothelial progenitor cells
  • Metronomic chemotherapy
  • Targeted therapies
  • Tumor angiogenesis
  • VEGF

ASJC Scopus subject areas

  • Cancer Research
  • Pharmaceutical Science

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