Cancer development, invasion, and metastasis is largely dependent on angiogenesis, the formation of new capillaries from pre-existing blood vessels, and this process is exquisitely regulated by a balance of pro- and anti-angiogenic factors. Stimulators of angiogenesis include growth factors, such as vascular endothelial growth factor (VEGF), a key promoter of vascular growth. Additionally, membrane-bound or extracellular matrix proteins, including thrombospondin-1 (TSP1), function as endogenous inhibitors of angiogenesis. In the case of cancer, the balance is altered, leading to a state of hyper-vascularization and allowing the tumor to establish its own blood supply. A quantitative description of the dynamic equilibrium of promoters and inhibitors of vascular growth would aid in our understanding of tumor angiogenesis and provide a platform to test cancer therapies that control this process. The proposed research aims to develop an experiment-based computational model of breast cancer angiogenesis that incorporates endogenous pro- and anti-angiogenic pathways (Aim 1). The model will be used to probe the mechanism by which TSP1 inhibits vascular growth and quantify the role of platelets in angiogenesis (Aim 2). Additionally, the model will simulate and predict the angiogenic response to breast cancer therapies, including VEGF-neutralizing agents and TSP1-derived anti- angiogenic peptides (Aim 3). This research will further our understanding of angiogenesis-related pathophysiology and facilitate the development and optimization of cancer therapies that inhibit tumor angiogenesis.

Public Health Relevance

More than 180,000 women are diagnosed with breast cancer each year. Cancer development, leading to invasion and metastasis, is largely governed by the cancer cells'ability to promote the growth of new blood vessels from pre-existing ones, a process called angiogenesis. This project aims to develop a quantitative model to study the balance of promoters and inhibitors of angiogenesis and apply the model to aid in the development of cancer therapeutics.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F14-C (20))
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Jakowlew, Sonia B
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Johns Hopkins University
Biomedical Engineering
Schools of Medicine
United States
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Finley, S D; Angelikopoulos, P; Koumoutsakos, P et al. (2015) Pharmacokinetics of Anti-VEGF Agent Aflibercept in Cancer Predicted by Data-Driven, Molecular-Detailed Model. CPT Pharmacometrics Syst Pharmacol 4:641-9
Finley, Stacey D; Chu, Liang-Hui; Popel, Aleksander S (2015) Computational systems biology approaches to anti-angiogenic cancer therapeutics. Drug Discov Today 20:187-97
Logsdon, Elizabeth A; Finley, Stacey D; Popel, Aleksander S et al. (2014) A systems biology view of blood vessel growth and remodelling. J Cell Mol Med 18:1491-508
Finley, Stacey D; Popel, Aleksander S (2013) Effect of tumor microenvironment on tumor VEGF during anti-VEGF treatment: systems biology predictions. J Natl Cancer Inst 105:802-11
Finley, Stacey D; Popel, Aleksander S (2012) Predicting the effects of anti-angiogenic agents targeting specific VEGF isoforms. AAPS J 14:500-9
Finley, Stacey D; Engel-Stefanini, Marianne O; Imoukhuede, P I et al. (2011) Pharmacokinetics and pharmacodynamics of VEGF-neutralizing antibodies. BMC Syst Biol 5:193