TY - JOUR
T1 - Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms
AU - Finley, Stacey D.
AU - Popel, Aleksander S.
N1 - Funding Information:
The authors thank Gang Liu and Spyridon Stamatelos for helpful discussions. This work was supported by National Institutes of Health grant R01 CA138264 (ASP) and fellowship F32 CA154213 (SDF), and the UNCF/Merck Postdoctoral Fellowship (SDF).
PY - 2012/9
Y1 - 2012/9
N2 - Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, whose effect on cancer growth and development is well characterized. Alternative splicing of VEGF leads to several different isoforms, which are differentially expressed in various tumor types and have distinct functions in tumor blood vessel formation. Many cancer therapies aim to inhibit angiogenesis by targeting VEGF and preventing intracellular signaling leading to tumor vascularization; however, the effects of targeting specific VEGF isoforms have received little attention in the clinical setting. In this work, we investigate the effects of selectively targeting a single VEGF isoform, as compared with inhibiting all isoforms. We utilize a molecular-detailed whole-body compartment model of VEGF transport and kinetics in the presence of breast tumor. The model includes two major VEGF isoforms, VEGF 121 and VEGF 165, receptors VEGFR1 and VEGFR2, and co-receptors Neuropilin-1 and Neuropilin-2. We utilize the model to predict the concentrations of free VEGF, the number of VEGF/VEGFR2 complexes (considered to be pro-angiogenic), and the receptor occupancy profiles following inhibition of VEGF using isoform-specific anti-VEGF agents. We predict that targeting VEGF 121 leads to a 54% and 84% reduction in free VEGF in tumors that secrete both VEGF isoforms or tumors that overexpress VEGF 121, respectively. Additionally, 21% of the VEGFR2 molecules in the blood are ligated following inhibition of VEGF 121, compared with 88% when both isoforms are targeted. Targeting VEGF 121 reduces tumor free VEGF and is an effective treatment strategy. Our results provide a basis for clinical investigation of isoform-specific anti-VEGF agents.
AB - Vascular endothelial growth factor (VEGF) is a key mediator of angiogenesis, whose effect on cancer growth and development is well characterized. Alternative splicing of VEGF leads to several different isoforms, which are differentially expressed in various tumor types and have distinct functions in tumor blood vessel formation. Many cancer therapies aim to inhibit angiogenesis by targeting VEGF and preventing intracellular signaling leading to tumor vascularization; however, the effects of targeting specific VEGF isoforms have received little attention in the clinical setting. In this work, we investigate the effects of selectively targeting a single VEGF isoform, as compared with inhibiting all isoforms. We utilize a molecular-detailed whole-body compartment model of VEGF transport and kinetics in the presence of breast tumor. The model includes two major VEGF isoforms, VEGF 121 and VEGF 165, receptors VEGFR1 and VEGFR2, and co-receptors Neuropilin-1 and Neuropilin-2. We utilize the model to predict the concentrations of free VEGF, the number of VEGF/VEGFR2 complexes (considered to be pro-angiogenic), and the receptor occupancy profiles following inhibition of VEGF using isoform-specific anti-VEGF agents. We predict that targeting VEGF 121 leads to a 54% and 84% reduction in free VEGF in tumors that secrete both VEGF isoforms or tumors that overexpress VEGF 121, respectively. Additionally, 21% of the VEGFR2 molecules in the blood are ligated following inhibition of VEGF 121, compared with 88% when both isoforms are targeted. Targeting VEGF 121 reduces tumor free VEGF and is an effective treatment strategy. Our results provide a basis for clinical investigation of isoform-specific anti-VEGF agents.
KW - angiogenesis
KW - cancer drug target
KW - computational model
KW - pharmacokinetic model
KW - systems biology
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U2 - 10.1208/s12248-012-9363-4
DO - 10.1208/s12248-012-9363-4
M3 - Article
C2 - 22547351
AN - SCOPUS:84862768329
SN - 1550-7416
VL - 14
SP - 500
EP - 509
JO - AAPS Journal
JF - AAPS Journal
IS - 3
ER -