4 OVERALL PROGRAM CRITIQUE: 4 PROGRAM LEADERSHIP: 6 PROGRAM AS AN INTEGRATED EFFORT: 6 PROJECT AND CORE SUMMARIES OF DISCUSSION: 7 VERTEBRATE ANIMALS (Resume): 8 ADDITIONAL REVIEW CONSIDERATIONS (Resume) 9 BUDGETARY OVERLAP: 9 COLLABORATING INSTITUTIONS: 9 REVISION NOTE: 9 PROJECT 1: Eph Receptor Targeting Strategies 10 PROJECT 2: Structural Features of Eph Receptor-Ephrin Interaction 19 PROJECT 3: Targeted Drug Delivery to Eph Receptor-Expressing Tumor Cells 28 CORE A: Eph Protein Expression 37 CORE B: Administrative 38 COMMITTEE BUDGET RECOMMENDATIONS 41 SPECIAL EMPHASIS PANEL ROSTER DESCRIPTION (provided by applicant): The Eph receptor tyrosine kinases have emerged as a new important family of cancer targets. Studies from several groups, including one from this program, have shown that disrupting the binding of Eph receptors with their ligands, the ephrins, inhibits tumor growth in preclinical mouse tumor models. Eph receptors that are upregulated in cancerous tissue can also be exploited for targeted drug delivery to tumors. Although binding interactions between Eph receptors and ephrin ligands are highly promiscuous, collaborative work between laboratories from this program has revealed that artificial ligands such as peptides and small molecules can bind selectively to the ephrin-binding pocket of different Eph receptors. Thus, specific targeting of individual Eph receptors can be achieved. However, only a few agents that inhibit ephrin binding have been identified so far. This program project aims to define the structural features conferring high affinity and controlling selectivity versus promiscuity of ligand binding to the Eph receptors as well as to optimize existing small molecule and peptide leads that inhibit Eph receptor-ephrin interaction. The anticancer effects of the optimized molecules will be evaluated using culture models and in vivo preclinical mouse cancer models. Close collaboration among the three participating laboratories, which have complementary expertise in Eph receptor biology and signal transduction, X-ray crystallography and biophysics, and NMR-based drug design and chemistry, will enable achievements that are beyond the immediate reaches of each individual component. Component 1 will evaluate strategies to modulate Eph receptor function in cancer cells and endothelial cells using chemical compounds and peptides optimized through the combined efforts of the program. Component 2 will use X-ray crystallography to characterize with high resolution the interfaces of Eph receptors in complex with high affinity peptide and small molecule ligands in comparison with the natural ephrin ligands. Component 3 will use NMR to characterize binding interfaces of Eph receptor domains in complex with chemical compounds and thus provide structural information enabling their optimization. Component 3 will also develop peptide-drug conjugates to selectively target cells expressing the EphA2 receptor in tumors, an approach complementary to using agents that interfere with Eph receptor/ephrin biological activities. The information obtained from the proposed studies is expected to enable development of new ways to effectively target the ephrin-binding pocket of Eph receptors using chemical compounds and peptides.
We expect that synergistic interactions within the program project will enable the development of new chemical compound- and peptide-based research tools that will be valuable to gain insight into the roles of individual Eph receptors in cancer as well as contribute to the discovery of new strategies to modulate Eph receptor activities to control cancer progression. Our studies proposing to disrupt Eph-ephrin protein interfaces complement drug discovery efforts under development in the pharmaceutical industry to target Eph receptors, which mainly revolve around the more traditional use of antibodies and kinase inhibitors.
|Singh, Deo R; Kanvinde, Pranjali; King, Christopher et al. (2018) The EphA2 receptor is activated through induction of distinct, ligand-dependent oligomeric structures. Commun Biol 1:15|
|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:|
|Wu, Bainan; De, Surya K; Kulinich, Anna et al. (2017) Potent and Selective EphA4 Agonists for the Treatment of ALS. Cell Chem Biol 24:293-305|
|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|
|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|
|Bhaskar, Archana; Tiwary, Bhupendra Nath (2016) Hypoxia inducible factor-1 alpha and multiple myeloma. Int J Adv Res (Indore) 4:706-715|
|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|
|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|
|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|
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