Breast cancer is the most commonly diagnosed female malignancy in the United States. Angiogenesis plays a critical role in tumorigenesis and metastasis in breast cancer. Thus, antiangiogenic therapies, either as monotherapy or in combination with other therapies are promising and being intensely investigated in both preclinical and clinical studies. The goal of the proposed project is to test novel endogenous antiangiogenic peptides in mouse models of human breast cancer. We will test peptides identified in our laboratory derived from three classes of proteins: thrombospondin type I repeat-containing proteins;CXC chemokines;and alpha5 fibrils of collagen type IV. We have performed careful in vitro screening of the identified peptides using endothelial cell proliferation and migration assays, and demonstrated activity in several in vivo assays in mice including subcutaneous basement-membrane-extract plugs, corneal micropocket, and tumor xenografts. Based on these studies, we have narrowed the selection to three leading peptides. We hypothesize that the identified peptides inhibit tumor angiogenesis in breast cancer and can therefore inhibit or significantly reduce the tumor growth. To test this hypothesis, we will examine antiangiogenic properties of the selected peptides using a mouse model of human breast cancer. Two human breast cancer cell lines, the less invasive MCF-7 and the more invasive MDA-MB-231, will be used to form orthotopic tumor xenografts in severe immune deficient (SCID) mice. The peptides will be administered intraperitoneally (i.p.) and tumor size will be monitored. In addition to naked peptides, peptides encapsulated into polymer nanomicelles will be used to increase their solubility, half-life, and enhance systemic administration. Tumor blood volume and vascular permeability will be monitored non-invasively using Magnetic Resonance Imaging (MRI). Immunohistochemistry will be performed to determine the effects on the vasculature and on the cancer and stromal cells. We have identified a number of peptide receptors on the endothelial cells in vitro using receptor neutralization by monoclonal antibodies. Specifically, we have identified receptors CD36, CD47, CXCR3, and beta-1 and beta-3 integrins. We will conduct studies on the expression of these receptors in tumor xenografts. We will also conduct pilot studies where we will apply the peptides in combination with other antiangiogenic agents (e.g., agents interfering with the VEGF pathways) and chemotherapeutic agents to test whether their action is additive or synergistic and if they can provide added therapeutic benefits. The proposed development of novel antiangiogenic agents would have a significant impact on research in tumor angiogenesis and other diseases associated with neovascularization.

Public Health Relevance

Breast cancer is the most commonly diagnosed female malignancy in the United States. Approximately 180,000 new cases of invasive breast cancer have been diagnosed in 2007. The relevance of this research to public health is that the work may lead to identification of new antiangiogenic agents (inhibiting abnormal blood vessel growth) for the treatment of breast cancer and potentially other forms of cancer. It will also provide a better understanding of the role of several tissue proteins in maintaining healthy vascular balance and how this role may change in disease conditions.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA131931-02
Application #
7779389
Study Section
Developmental Therapeutics Study Section (DT)
Program Officer
Forry, Suzanne L
Project Start
2009-03-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$180,400
Indirect Cost
Name
Johns Hopkins University
Department
Biomedical Engineering
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Koskimaki, Jacob E; Lee, Esak; Chen, William et al. (2013) Synergy between a collagen IV mimetic peptide and a somatotropin-domain derived peptide as angiogenesis and lymphangiogenesis inhibitors. Angiogenesis 16:159-70
Rosca, Elena Victoria; Lal, Bachchu; Koskimaki, Jacob E et al. (2012) Collagen IV and CXC chemokine-derived antiangiogenic peptides suppress glioma xenograft growth. Anticancer Drugs 23:706-12
Rosca, Elena V; Koskimaki, Jacob E; Pandey, Niranjan B et al. (2012) Structure-activity relationship study of collagen-derived anti-angiogenic biomimetic peptides. Chem Biol Drug Des 80:27-37
Rosca, Elena V; Koskimaki, Jacob E; Rivera, Corban G et al. (2011) Anti-angiogenic peptides for cancer therapeutics. Curr Pharm Biotechnol 12:1101-16
Lee, Esak; Rosca, Elena V; Pandey, Niranjan B et al. (2011) Small peptides derived from somatotropin domain-containing proteins inhibit blood and lymphatic endothelial cell proliferation, migration, adhesion and tube formation. Int J Biochem Cell Biol 43:1812-21
Rosca, Elena V; Koskimaki, Jacob E; Pandey, Niranjan B et al. (2011) Development of a biomimetic peptide derived from collagen IV with anti-angiogenic activity in breast cancer. Cancer Biol Ther 12:808-17
Koskimaki, Jacob E; Karagiannis, Emmanouil D; Rosca, Elena V et al. (2009) Peptides derived from type IV collagen, CXC chemokines, and thrombospondin-1 domain-containing proteins inhibit neovascularization and suppress tumor growth in MDA-MB-231 breast cancer xenografts. Neoplasia 11:1285-91