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 language | English |
|---|---|
| Pages (from-to) | 551-559 |
| Number of pages | 9 |
| Journal | Current Cancer Drug Targets |
| Volume | 5 |
| Issue number | 7 |
| DOIs | |
| Publication status | Published - Nov 2005 |
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Keywords
- Antiangiogenic drugs
- Circulating endothelial progenitor cells
- Metronomic chemotherapy
- Targeted therapies
- Tumor angiogenesis
- VEGF
ASJC Scopus subject areas
- Cancer Research
- Pharmaceutical Science
Cite this
Cellular and molecular surrogate markers to monitor targeted and non-targeted antiangiogenic drug activity and determine optimal biologic dose. / Shaked, Yuval; Bocci, Guido; Munoz, Raquel; Man, Shan; Ebos, J. M L; Hicklin, Daniel J.; Bertolini, Francesco; D'Amato, Robert; Kerbel, Robert S.
In: Current Cancer Drug Targets, Vol. 5, No. 7, 11.2005, p. 551-559.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cellular and molecular surrogate markers to monitor targeted and non-targeted antiangiogenic drug activity and determine optimal biologic dose
AU - Shaked, Yuval
AU - Bocci, Guido
AU - Munoz, Raquel
AU - Man, Shan
AU - Ebos, J. M L
AU - Hicklin, Daniel J.
AU - Bertolini, Francesco
AU - D'Amato, Robert
AU - Kerbel, Robert S.
PY - 2005/11
Y1 - 2005/11
N2 - 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.
AB - 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.
KW - Antiangiogenic drugs
KW - Circulating endothelial progenitor cells
KW - Metronomic chemotherapy
KW - Targeted therapies
KW - Tumor angiogenesis
KW - VEGF
UR - http://www.scopus.com/inward/record.url?scp=27144468094&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27144468094&partnerID=8YFLogxK
U2 - 10.2174/156800905774574020
DO - 10.2174/156800905774574020
M3 - Article
C2 - 16305351
AN - SCOPUS:27144468094
VL - 5
SP - 551
EP - 559
JO - Current Cancer Drug Targets
JF - Current Cancer Drug Targets
SN - 1568-0096
IS - 7
ER -