The Eph receptor tyrosine kinases have emerged as a new important family of cancer targets. Many Eph receptors are frequently upregulated in cancer cells and some of them are also present in the tumor microenvironment. Furthermore, modulating the activity of these receptors has been shown to affect tumor growth and metastatic spread. Several studies have demonstrated that disrupting the binding of Eph receptors to their ligands, the ephrins, in preclinical mouse tumor models results in decreased tumor growth, which is likely due at least in part to inhibition of tumor angiogenesis. However, Eph-based anticancer strategies will have to take into account the multiplicity of mechanisms through which Eph receptors affect the malignant properties of cancer cells. Furthermore, it will be important to determine the characteristics of tumors that are most sensitive to inhibitors of Eph-ephrin binding versus those of tumors where these inhibitors may not be as effective. Binding interactions between Eph receptors and their ligands, the ephrins, are highly promiscuous. Despite this promiscuity in the recognition of their natural ephrin ligands, our work in collaboration with other components of this program has revealed that the high affinity ephrin-binding pockets of different Eph receptors show selectivity for artificial ligands such as chemical compounds and peptides, demonstrating that exquisitely specific targeting of individual Eph receptors can be achieved. The proposed studies aim to evaluate the effects of inhibitors of Eph receptor-ephrin binding on endothelial cells and cancer cells, determine whether the effects on cancer cells depend on the cellular context, and identify the characteristics of the tumor cells for which these inhibitors are most effective. This information will allow matching of particular Eph-based therapeutic strategies to the tumor characteristics. Cultured cancer cell lines will be used to evaluate the activities of monomeric soluble forms of Eph receptor ligand binding domains as prototypes for inhibitors of Eph receptor-ephrin binding. Furthermore, we will evaluate in cell culture and tumor xenografts Eph receptor-targeting small molecules and peptides to be collaboratively developed with the other components of the program project In particular, structural information will be used to improve the binding aftlnlty of previously identified small molecule and peptide leads that target the ligand-binding pocket of Eph receptors and inhibit ephrin binding.

Public Health Relevance

The proposed studies aim to develop new strategies to modulate Eph receptor activities to control cancer progression as well as to identify new chemical and peptide-based molecular probes that can be used to gain insight into the biology of Eph receptors in cancer. Our studies proposing to disrupt Eph-ephrin protein interfaces complement drug discovery efforts underway in the pharmaceutical industry to target Eph receptors, which mainly revolve around the more traditional use of antibodies and kinase inhibitors

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA138390-02
Application #
8215266
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
2
Fiscal Year
2011
Total Cost
$441,467
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Singh, Deo R; Ahmed, Fozia; Paul, Michael D et al. (2017) The SAM domain inhibits EphA2 interactions in the plasma membrane. Biochim Biophys Acta 1864:31-38
Stammes, Marieke A; Prevoo, Hendrica A J M; Ter Horst, Meyke C et al. (2017) Evaluation of EphA2 and EphB4 as Targets for Image-Guided Colorectal Cancer Surgery. Int J Mol Sci 18:
Singec, Ilyas; Crain, Andrew M; Hou, Junjie et al. (2016) Quantitative Analysis of Human Pluripotency and Neural Specification by In-Depth (Phospho)Proteomic Profiling. Stem Cell Reports 7:527-542
Bhaskar, Archana; Tiwary, Bhupendra Nath (2016) Hypoxia inducible factor-1 alpha and multiple myeloma. Int J Adv Res (Indore) 4:706-715
Pasquale, Elena B (2016) Exosomes expand the sphere of influence of Eph receptors and ephrins. J Cell Biol 214:5-7
Barquilla, Antonio; Lamberto, Ilaria; Noberini, Roberta et al. (2016) Protein kinase A can block EphA2 receptor-mediated cell repulsion by increasing EphA2 S897 phosphorylation. Mol Biol Cell 27:2757-70
Singh, Deo R; Pasquale, Elena B; Hristova, Kalina (2016) A small peptide promotes EphA2 kinase-dependent signaling by stabilizing EphA2 dimers. Biochim Biophys Acta 1860:1922-8
Singh, Deo R; Cao, QingQing; King, Christopher et al. (2015) Unliganded EphA3 dimerization promoted by the SAM domain. Biochem J 471:101-9
Wu, Bainan; Wang, Si; De, Surya K et al. (2015) Design and Characterization of Novel EphA2 Agonists for Targeted Delivery of Chemotherapy to Cancer Cells. Chem Biol 22:876-887
Barquilla, Antonio; Pasquale, Elena B (2015) Eph receptors and ephrins: therapeutic opportunities. Annu Rev Pharmacol Toxicol 55:465-87

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