Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms

Stacey D. Finley, Aleksander S Popel

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)500-509
Number of pages10
JournalAAPS Journal
Volume14
Issue number3
DOIs
StatePublished - Sep 2012

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Vascular Endothelial Growth Factor A
Protein Isoforms
Neoplasms
Neuropilin-2
Neuropilin-1
Vascular Tissue Neoplasms
Vascular Endothelial Growth Factor Receptor
Angiogenesis Inducing Agents
Alternative Splicing
Growth and Development

Keywords

  • angiogenesis
  • cancer drug target
  • computational model
  • pharmacokinetic model
  • systems biology

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms. / Finley, Stacey D.; Popel, Aleksander S.

In: AAPS Journal, Vol. 14, No. 3, 09.2012, p. 500-509.

Research output: Contribution to journalArticle

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