The Eph receptors represent the largest subgroup of the receptor tyrosine kinase (RTK) and they influence cell shape and migration by acting directly on the actin cytoskeleton. In addition, they can affect cell proliferation and survival. In view of their pivotal role in cell-migration and cell-cell interaction, it is not surprising that Eph receptors and ephrins play an important role in tumor growth and cancer cell metastasis. Elevated expression of certain Eph receptors and ephrins has indeed been associated with tumor angiogenesis in many types of cancers. Therefore, there is strong evidence that Eph receptor/ephrin signaling could provide a novel yet unexplored target for the development of effective anti-cancer treatments. Because many Eph receptors are also overexpressed in cancer cells, they could also be used as targets to deliver cytotoxic or anti-cancer agents selectively to the tumors. In fact, following binding of their ephrin ligands, the Eph receptors are actively internalized in the cell where are directed into lysosomes. Hence, our central hypothesis is that Eph receptor targeting ligands covalently linked to a variety of anti-cancer agents could represent novel and effective therapeutics that would selectively deliver cytotoxic agents to cancer cells via the Eph receptors. In particular, we will explore the ability of a selective peptide ligand to deliver toxic substances to cancer cells expressing the EphA2 receptor. Furthermore, we will explore a novel and alternative way to target the EphA4 receptor by direct targeting of its ligand binding domain. To achieve these goals we will combine modern medicinal chemistry with structure-based design, cancer cell biology and in vitro and in vivo pharmacology. Finally, the most promising compounds will be evaluated in cellular assays and ultimately in tumor xenograft studies with breast, lung and prostate cancer cell lines as well as endothelial cells. If proven successful, our studies may result in novel agents that would not only be more efficacious than the current chemotherapeutic compounds, but that would also enhance the quality of life during and after chemotherapy.

Public Health Relevance

The Eph receptors are a class of proteins that are abundantly expressed on the surface of cancer cells and provide the opportunity to differentiate normal from diseased cells. Hence, our work is centered on the development of novel strategies to deliver potent cytotoxic drugs selectively to cancer cells by targeting the Eph receptors. If successful, our research would open the way to the development of more efficacious novel anti-cancer agents that would also enhance the quality of life during and after chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA138390-04
Application #
8448019
Study Section
Special Emphasis Panel (ZCA1-GRB-P)
Project Start
Project End
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
4
Fiscal Year
2013
Total Cost
$346,984
Indirect Cost
$104,283
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
020520466
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Hassan-Mohamed, I; Giorgio, C; Incerti, M et al. (2014) UniPR129 is a competitive small molecule Eph-ephrin antagonist blocking in vitro angiogenesis at low micromolar concentrations. Br J Pharmacol 171:5195-208
Vargas, Lina M; Leal, Nancy; Estrada, Lisbell D et al. (2014) EphA4 activation of c-Abl mediates synaptic loss and LTP blockade caused by amyloid-? oligomers. PLoS One 9:e92309
Lamberto, Ilaria; Lechtenberg, Bernhard C; Olson, Erika J et al. (2014) Development and structural analysis of a nanomolar cyclic peptide antagonist for the EphA4 receptor. ACS Chem Biol 9:2787-95
Barile, Elisa; Wang, Si; Das, Swadesh K et al. (2014) Design, synthesis and bioevaluation of an EphA2 receptor-based targeted delivery system. ChemMedChem 9:1403-12
Incerti, Matteo; Tognolini, Massimiliano; Russo, Simonetta et al. (2013) Amino acid conjugates of lithocholic acid as antagonists of the EphA2 receptor. J Med Chem 56:2936-47
Wang, Si; Noberini, Roberta; Stebbins, John L et al. (2013) Targeted delivery of paclitaxel to EphA2-expressing cancer cells. Clin Cancer Res 19:128-37
Mercurio, Flavia A; Marasco, Daniela; Pirone, Luciano et al. (2013) Heterotypic Sam-Sam association between Odin-Sam1 and Arap3-Sam: binding affinity and structural insights. Chembiochem 14:100-6
Duggineni, Srinivas; Mitra, Sayantan; Noberini, Roberta et al. (2013) Design, synthesis and characterization of novel small molecular inhibitors of ephrin-B2 binding to EphB4. Biochem Pharmacol 85:507-13
Wu, Bainan; Zhang, Ziming; Noberini, Roberta et al. (2013) HTS by NMR of combinatorial libraries: a fragment-based approach to ligand discovery. Chem Biol 20:19-33
Duggineni, Srinivas; Mitra, Sayantan; Lamberto, Ilaria et al. (2013) Design and Synthesis of Potent Bivalent Peptide Agonists Targeting the EphA2 Receptor. ACS Med Chem Lett 4:

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