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

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-mole...

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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
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container_issue 16_Supplement
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container_title Cancer research (Chicago, Ill.)
container_volume 80
creator 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
description 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
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fullrecord <record><control><sourceid>crossref</sourceid><recordid>TN_cdi_crossref_primary_10_1158_1538_7445_AM2020_122</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>10_1158_1538_7445_AM2020_122</sourcerecordid><originalsourceid>FETCH-crossref_primary_10_1158_1538_7445_AM2020_1223</originalsourceid><addsrcrecordid>eNqdj8FOwzAQRC0EEgH6Bxz2B9Larq1G3FqUigucerc2iZO6Ck6061L170kE4gM4jWY0I70R4lnJpVK2WCm7LvKNMXa5fddSy1xpfSOyv_hWZFLKIrdmo-_FA_NpslZJm4lqW3EirBNMmxc4IHU-hdhBO9AFqQGMDZD_8sQeyvG4M6ty_7HTwKGL2M_N6goIox9TaDxcQjpCc8Ye2nOsUxgiP4m7Fnv2i199FGZfHl7f8poGZvKtGyl8Il2dkm7-42ZwN4O7nz9uYlv_c_YNTE1S-w</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype></control><display><type>article</type><title>Abstract 122: Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions</title><source>EZB Electronic Journals Library</source><creator>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</creator><creatorcontrib>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</creatorcontrib><description>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&lt;0.05). In vivo, BIDEN-AP and CCPM-BIDEN-AP significantly reduced tumor weight (p&lt;0.05) and number of tumor nodules (p&lt;0.01) of intraperitoneally inoculated A2780cp20 ovarian tumors. Moreover, CCPM-BIDEN-AP displayed greater anti-tumor potency than BIDEN-AP with regard to reduction in the number of tumor nodules (p&lt;0.01). Both BIDEN-AP and CCPM-BIDEN-AP compromised angiogenesis as evidenced by significantly reduced microvessel density (p&lt;0.01). Conclusion: Given the robust anti-tumor effects of BIDEN-AP, these data could have direct relevance for further therapeutic development. Citation Format: Chiyi Xiong, Yunfei Wen, Jun Zhao, Dengke Yin, Lingyun Xu, Anca Chelariu-Raicu, Cody Yao, Xiaohong Leng, Jinsong Liu, Rajan R Chaudhari, Shuxing Zhang, Anil K Sood, Chun Li. Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 122.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/1538-7445.AM2020-122</identifier><language>eng</language><ispartof>Cancer research (Chicago, Ill.), 2020-08, Vol.80 (16_Supplement), p.122-122</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids></links><search><creatorcontrib>Xiong, Chiyi</creatorcontrib><creatorcontrib>Wen, Yunfei</creatorcontrib><creatorcontrib>Zhao, Jun</creatorcontrib><creatorcontrib>Yin, Dengke</creatorcontrib><creatorcontrib>Xu, Lingyun</creatorcontrib><creatorcontrib>Chelariu-Raicu, Anca</creatorcontrib><creatorcontrib>Yao, Cody</creatorcontrib><creatorcontrib>Leng, Xiaohong</creatorcontrib><creatorcontrib>Liu, Jinsong</creatorcontrib><creatorcontrib>Chaudhari, Rajan R</creatorcontrib><creatorcontrib>Zhang, Shuxing</creatorcontrib><creatorcontrib>Sood, Anil K</creatorcontrib><creatorcontrib>Li, Chun</creatorcontrib><title>Abstract 122: Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions</title><title>Cancer research (Chicago, Ill.)</title><description>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&lt;0.05). In vivo, BIDEN-AP and CCPM-BIDEN-AP significantly reduced tumor weight (p&lt;0.05) and number of tumor nodules (p&lt;0.01) of intraperitoneally inoculated A2780cp20 ovarian tumors. Moreover, CCPM-BIDEN-AP displayed greater anti-tumor potency than BIDEN-AP with regard to reduction in the number of tumor nodules (p&lt;0.01). Both BIDEN-AP and CCPM-BIDEN-AP compromised angiogenesis as evidenced by significantly reduced microvessel density (p&lt;0.01). Conclusion: Given the robust anti-tumor effects of BIDEN-AP, these data could have direct relevance for further therapeutic development. Citation Format: Chiyi Xiong, Yunfei Wen, Jun Zhao, Dengke Yin, Lingyun Xu, Anca Chelariu-Raicu, Cody Yao, Xiaohong Leng, Jinsong Liu, Rajan R Chaudhari, Shuxing Zhang, Anil K Sood, Chun Li. Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. 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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&lt;0.05). In vivo, BIDEN-AP and CCPM-BIDEN-AP significantly reduced tumor weight (p&lt;0.05) and number of tumor nodules (p&lt;0.01) of intraperitoneally inoculated A2780cp20 ovarian tumors. Moreover, CCPM-BIDEN-AP displayed greater anti-tumor potency than BIDEN-AP with regard to reduction in the number of tumor nodules (p&lt;0.01). Both BIDEN-AP and CCPM-BIDEN-AP compromised angiogenesis as evidenced by significantly reduced microvessel density (p&lt;0.01). Conclusion: Given the robust anti-tumor effects of BIDEN-AP, these data could have direct relevance for further therapeutic development. Citation Format: Chiyi Xiong, Yunfei Wen, Jun Zhao, Dengke Yin, Lingyun Xu, Anca Chelariu-Raicu, Cody Yao, Xiaohong Leng, Jinsong Liu, Rajan R Chaudhari, Shuxing Zhang, Anil K Sood, Chun Li. Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 122.</abstract><doi>10.1158/1538-7445.AM2020-122</doi></addata></record>
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title Abstract 122: Targeting forward and reverse EphB4/EFNB2 signaling by a peptide with dual functions
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