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 #
5P01CA138390-05
Application #
8611712
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Sanford-Burnham Medical Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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 7:527-42
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
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
Bhaskar, Archana; Tiwary, Bhupendra Nath (2016) Hypoxia inducible factor-1 alpha and multiple myeloma. Int J Adv Res (Indore) 4:706-715
Riedl, Stefan J; Pasquale, Elena B (2015) Targeting the Eph System with Peptides and Peptide Conjugates. Curr Drug Targets 16:1031-47
Singh, Deo R; Ahmed, Fozia; King, Christopher et al. (2015) EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling. J Biol Chem 290:27271-9
Bhatia, Shilpa; Hirsch, Kellen; Baig, Nimrah A et al. (2015) Effects of altered ephrin-A5 and EphA4/EphA7 expression on tumor growth in a medulloblastoma mouse model. J Hematol Oncol 8:105
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 22:876-87
Forse, Garry Jason; Uson, Maria Loressa; Nasertorabi, Fariborz et al. (2015) Distinctive Structure of the EphA3/Ephrin-A5 Complex Reveals a Dual Mode of Eph Receptor Interaction for Ephrin-A5. PLoS One 10:e0127081

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