Abstract 122: Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.122-122
• Main Authors: Xiong, Chiyi, Wen, Yunfei, Zhao, Jun, Yin, Dengke, Xu, Lingyun, Chelariu-Raicu, Anca, Yao, Cody, Leng, Xiaohong, Liu, Jinsong, Chaudhari, Rajan R, Zhang, Shuxing, Sood, Anil K, Li, Chun
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-122

Introduction: EphB4 is frequently overexpressed in ovarian and other solid tumors and involved in interactions between tumor cells and tumor microenvironment, contributing to metastasis. EphB4 and its membrane-bound ligand ephrin B2 (EFNB2) mediates bi-directional signaling. Currently, no small-molecule-based, peptides with dual functional binding to EphB4 are available. Therefore, we developed an EphB4 agonist that is capable of activating the forward EphB4 signaling and interfering with the reverse EFNB2 signaling. Methods: A high-affinity bi-directional ephrin agonist peptide (BIDEN-AP) that selectively activated EphB4 was discovered through structural modifications to the known EphB4 antagonist TNYLFSPNGPIARAW (TNYL-RAW) by surface plasma resonance and cell based assays. To improve pharmacokinetics and enhance peptide stability, BINDEN-AP peptide was conjugated to Core-Crosslinked Polymeric Micelles (CCPM). Anti-tumor and anti-angiogenic effects of BINDEN-AP peptide and its conjugate with CCPM were evaluated using orthotopic human A2789cp20-Luc ovarian cancer xenograft model, and PDX model of high grade serous ovarian carcinoma (HGSC). Results: We found that BIDEN-AP was selectively internalized via receptor-mediated endocytosis, mediated phosphorylation of EphB4 and its downstream adaptor protein Crk1 (MAPK14), and suppressed invasion and epithelial-to-mesenchymal transition in ovarian cancer cells. BIDEN-AP also inhibited endothelial migration and tube formation by 50% (p