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Monitoring Functionality and Morphology of Vasculature Recruited by Factors Secreted by Fast-growing Tumor-generating Cells
Published on: November 23, 2014
Quantitative insight in utilizing circulating angiogenic factors as biomarkers for antiangiogenic therapy: systems
1Department of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA.
Abstract:
Circulating angiogenic factors (CAF) like vascular endothelial growth factor (VEGF), placental growth factor (PlGF), and sVEGFR2 have potential as biomarkers for antiangiogenic therapy. The interpretation of changes in CAF is complicated by the dynamic nature of the tumor and host cells emanating CAF in response to VEGF pathway inhibition. We developed a systems pharmacology model of anti-VEGF agents to investigate CAF modulation by tumor and host cells, and the relationship between overall CAF changes in response to sunitinib and antitumor efficacy. This model distinguishes between the tumor cells' contributions from tumor-independent response to therapy and total plasma CAF correlating with antitumor activity. Altered VEGF is more likely to serve as a useful biomarker reflecting tumor responses in cancer patients whose pretreatment VEGF is higher than baseline VEGF in healthy subjects. Our findings provide a mechanistic insight into tumor modulation of angiogenic molecules, and may explain the inconsistent results found in previous biomarker studies.
Insights
This study models anti-VEGF therapy, revealing tumor and host cells dynamically alter circulating angiogenic factors (CAFs). Understanding these changes helps clarify CAF biomarker use in cancer treatment.
Area of Science:
- Pharmacology
- Biomarker Discovery
- Cancer Research
Background:
- Circulating angiogenic factors (CAFs) like VEGF, PlGF, and sVEGFR2 are potential biomarkers for antiangiogenic therapy.
- Tumor and host cell responses to VEGF pathway inhibition complicate CAF interpretation.
- Dynamic CAF modulation by tumor and host cells requires mechanistic understanding.
Purpose of the Study:
- To develop a systems pharmacology model to investigate CAF modulation by tumor and host cells during anti-VEGF therapy.
- To explore the relationship between overall CAF changes and antitumor efficacy in response to sunitinib.
- To differentiate tumor cell contributions from tumor-independent responses in total plasma CAF.
Main Methods:
- Developed a systems pharmacology model for anti-VEGF agents.
- Simulated CAF dynamics in response to VEGF pathway inhibition.
- Correlated modeled CAF changes with simulated antitumor activity.
Main Results:
- The model differentiates CAF contributions from tumor cells versus tumor-independent responses.
- Altered VEGF is a more reliable biomarker in patients with higher pretreatment VEGF levels.
- Mechanistic insights into tumor modulation of angiogenic molecules were provided.
Conclusions:
- Tumor and host cells dynamically modulate circulating angiogenic factors during anti-VEGF therapy.
- Understanding these modulations is crucial for interpreting CAF biomarker data.
- The model offers explanations for inconsistent results in previous CAF biomarker studies.
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