The overall objective of this proposal is to test whether EphA2 kinase agonists can inhibit prostate cancer progression through novel negative signaling pathways identified in the applicant's laboratory. There are two basic steps in tumor metastasis: one is tumor cell dissemination and the other is growth at distal sites. Cell motility is central to tumor cell dissemination, while metastatic growth is governed by autocrine and paracrine factors that frequently converge on Ras/MAPK signaling pathway. Therefore, agents that can inhibit either cell motility or suppress MAPK activation are potential candidates for anti-cancer drug discovery. The applicant's laboratory demonstrates that EphA2 receptor tyrosine kinase (RTK) can inhibit cell migration by targeting integrins and focal adhesion kinase, and attenuate Ras/MAPK cascade by lowering Ras GTP loading. Moreover, in both human and canine prostate cancer (PCa), EphA2 expression is correlated with tumor progression. These data suggest that EphA2 is a novel target to prevent progression of PCa. To this end, a small EphA2-binding peptide (EP1) has been isolated from phage display libraries. Functionally, EP1 mirrors ephrin-A1 in its ability to suppress cell motility and growth, establishing the feasibility of targeting EphA2 with small molecules.
The aims of this proposal are: 1) To validate EphA2 as an anti-cancer progression target in vivo. Initial studies will assess how EphA2 agonists affect subcutaneous tumor growth of green fluorescence protein (GFP)- tagged PC-3 cells. In the second phase studies, GFP-PC-3 cells will be implanted orthotopically to determine the effects of EphA2 agonists on metastasis, which will be monitored in part by whole body imaging in live animals, and by organ imaging at necropsy using fluorescence stereomicroscope. 2) To determine X- ray crystallographic structure of EphA2 ligand-binding domain in complex with ephrin-A1 or EP-1 peptide. The structural information will be used to guide the selection of smaller and more potent peptide agonists. 3) To identify the effectors which mediate the inhibitory effects of EphA2 activation on Ras/MAPK pathway. Completion of the proposed studies can lead to new mechanism-based therapeutic agents and strategies for prostate cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092259-03
Application #
6711809
Study Section
Metabolic Pathology Study Section (MEP)
Program Officer
Sussman, Daniel J
Project Start
2002-04-01
Project End
2008-03-31
Budget Start
2004-06-09
Budget End
2005-03-31
Support Year
3
Fiscal Year
2004
Total Cost
$82,553
Indirect Cost
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Guo, Hong; Miao, Hui; Gerber, Lizabeth et al. (2006) Disruption of EphA2 receptor tyrosine kinase leads to increased susceptibility to carcinogenesis in mouse skin. Cancer Res 66:7050-8
Lakhe-Reddy, Sujata; Khan, Shenaz; Konieczkowski, Martha et al. (2006) Beta8 integrin binds Rho GDP dissociation inhibitor-1 and activates Rac1 to inhibit mesangial cell myofibroblast differentiation. J Biol Chem 281:19688-99
Miao, Hui; Strebhardt, Klaus; Pasquale, Elena B et al. (2005) Inhibition of integrin-mediated cell adhesion but not directional cell migration requires catalytic activity of EphB3 receptor tyrosine kinase. Role of Rho family small GTPases. J Biol Chem 280:923-32
Miao, Hui; Nickel, Christian H; Cantley, Lloyd G et al. (2003) EphA kinase activation regulates HGF-induced epithelial branching morphogenesis. J Cell Biol 162:1281-92

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