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Pharmaceuticals
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Targeting the Eph–ephrin System
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Targeting the Eph–ephrin System

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (31 March 2020) | Viewed by 32471

Special Issue Editor

Prof. Dr. Simona Bertoni

E-Mail Website
Guest Editor
Department of Food and Drug, University of Parma, Parco Area delle Scienze 27/a, 43124 Parma, Italy
Interests: Pharmacology; intestinal inflammation; Eph-ephrin system; Eph-ephrin ligands; cholinergic receptors; mesenteric ischemia-reperfusion; serotonin and histamine ligands

Special Issue Information

Dear Colleagues,

The interest in the Eph–ephrin system has significantly and progressively grown during the last 25 years, as testified by the exponential rise in the number of scientific articles dealing with Eph receptors and their ephrin ligands from 1994 onwards. Eph receptor tyrosine kinases and their ephrin counterparts, comprising A- and B-type ephrins, uniquely stand out for their contact-dependent bidirectional signalling in neighbouring Eph- and ephrin-bearing cells. Largely involved in cellular proliferation and adhesion/repulsion responses, the Eph–ephrin system has a foremost role during embryonic life in regulating morphogenesis and organogenesis. Moreover, as it is now increasingly emerging, it is crucial in tissue regeneration/remodelling and in cancer progression and angiogenesis in post-natal life. Intriguingly, in the adult, this signalling pathway is also involved in several other pathophysiological conditions, such as inflammation and atherosclerosis, neurological disorders, diabetes, and bone diseases.

Proposed strategies to pharmacologically modulate Eph–ephrin signalling pathways include agonists, such as anti-Eph monoclonal antibodies and dimeric Fc-conjugated Eph–ephrin proteins, and antagonists, such as kinase inhibitors and protein–protein interaction inhibitors, some of which are already being tested in clinical studies. However, several problems, including the promiscuity of Eph–ephrin interactions, the complexity of Eph–ephrin intracellular signalling, and the sometimes disparate cellular outcomes that are triggered, have hindered up to now the full clinical exploitation of the available candidate drugs.

The present Special Issue of Pharmaceuticals is focused on “Targeting the Eph–ephrin system” and it aims to be an up-to-date collection of manuscripts and review articles dealing with the manifold challenges posed by this signalling pathway. The proposed topics will comprise the role of Eph–ephrin forward and reverse signaling, kinase-dependent and -independent signaling, Eph–ephrin system in cancer and non-cancer pathologies, and therapeutic strategies to target and modulate Eph–ephrin pathways. This Special Issue will mirror the state of the art in this field of investigation and will help to highlight original lines of research.

I warmly hope that you will be able to submit your valuable contribution as an original article or review dealing with research in this area of investigation.

Prof. Bertoni Simona
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (7 papers)

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Research

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13 pages, 2466 KiB  
Article
Evaluation of EphB4 as Target for Image-Guided Surgery of Breast Cancer
by Cansu de Muijnck, Yoren van Gorkom, Maurice van Duijvenvoorde, Mina Eghtesadi, Geeske Dekker-Ensink, Shadhvi S. Bhairosingh, Alessandra Affinito, Peter J. K. Kuppen, Alexander L. Vahrmeijer and Cornelis F. M. Sier
Pharmaceuticals 2020, 13(8), 172; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13080172 - 30 Jul 2020
Cited by 1 | Viewed by 3954
Abstract
Background: Targeted image-guided surgery is based on the detection of tumor cells after administration of a radio-active or fluorescent tracer. Hence, enhanced binding of a tracer to tumor tissue compared to healthy tissue is crucial. Various tumor antigens have been evaluated as possible [...] Read more.
Background: Targeted image-guided surgery is based on the detection of tumor cells after administration of a radio-active or fluorescent tracer. Hence, enhanced binding of a tracer to tumor tissue compared to healthy tissue is crucial. Various tumor antigens have been evaluated as possible targets for image-guided surgery of breast cancer, with mixed results. Methods: In this study we have evaluated tyrosine kinase receptor EphB4, a member from the Eph tyrosine kinase receptor family, as a possible target for image-guided surgery of breast cancers. Two independent tissue micro arrays, consisting of matched sets of tumor and normal breast tissue, were stained for EphB4 by immunohistochemistry. The intensity of staining and the percentage of stained cells were scored by two independent investigators. Results: Immunohistochemical staining for EphB4 shows that breast cancer cells display enhanced membranous expression compared to adjacent normal breast tissue. The enhanced tumor staining is not associated with clinical variables like age of the patient or stage or subtype of the tumor, including Her2-status. Conclusion: These data suggest that EphB4 is a promising candidate for targeted image-guided surgery of breast cancer, especially for Her2 negative cases. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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13 pages, 2006 KiB  
Article
Therapeutic Targeting of Pancreatic Cancer via EphA2 Dimeric Agonistic Agents
by Ahmed F. Salem, Luca Gambini, Parima Udompholkul, Carlo Baggio and Maurizio Pellecchia
Pharmaceuticals 2020, 13(5), 90; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13050090 - 10 May 2020
Cited by 9 | Viewed by 3662
Abstract
Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of dimeric compounds at the structural, biochemical, and [...] Read more.
Recently, we reported on potent EphA2 targeting compounds and demonstrated that dimeric versions of such agents can exhibit remarkably increased agonistic activity in cellular assays compared to the monomers. Here we further characterize the activity of dimeric compounds at the structural, biochemical, and cellular level. In particular, we propose a structural model for the mechanism of receptor activation by dimeric agents and characterize the effect of most potent compounds in inducing EphA2 activation and degradation in a pancreatic cancer cell line. These cellular studies indicate that the pro-migratory effects induced by the receptor can be reversed in EphA2 knockout cells, by treatment with either a dimeric natural ligand (ephrinA1-Fc), or by our synthetic agonistic dimers. Based on these data we conclude that the proposed agents hold great potential as possible therapeutics in combination with standard of care, where these could help suppressing a major driver for cell migration and tumor metastases. Finally, we also found that, similar to ephrinA1-Fc, dimeric agents cause a sustained internalization of the EphA2 receptor, hence, with proper derivatizations, these could also be used to deliver chemotherapy selectively to pancreatic tumors. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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17 pages, 2672 KiB  
Article
Drug Conjugates for Targeting Eph Receptors in Glioblastoma
by Puja Sharma, Callie Roberts, Denise Herpai, Izabela D. Fokt, Waldemar Priebe and Waldemar Debinski
Pharmaceuticals 2020, 13(4), 77; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13040077 - 23 Apr 2020
Cited by 7 | Viewed by 4884
Abstract
Glioblastoma (GBM) is a complex and heterogeneous tumor that warrants a comprehensive therapeutic approach for treatment. Tumor-associated antigens offer an opportunity to selectively target various components of the GBM microenvironment while sparing the normal cells within the central nervous system. In this study, [...] Read more.
Glioblastoma (GBM) is a complex and heterogeneous tumor that warrants a comprehensive therapeutic approach for treatment. Tumor-associated antigens offer an opportunity to selectively target various components of the GBM microenvironment while sparing the normal cells within the central nervous system. In this study, we conjugated a multivalent vector protein, QUAD 3.0, that can target four receptors: EphA3, EphA2, EphB2, and also IL-13RA2, spanning virtually 100% of the GBM microenvironment, to doxorubicin derivatives. The conjugates effectively bound to all four receptors, although to varying degrees, and delivered cytotoxic loads to both established and patient-derived GBM cell lines, with IC50 values in the low nM range. The conjugates were also non-toxic to animals. We anticipate that the QUAD 3.0 Dox conjugates will be further used in preclinical models and possibly clinics in the foreseeable future. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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11 pages, 1029 KiB  
Article
Evaluation of the Anti-Tumor Activity of Small Molecules Targeting Eph/Ephrins in APC min/J Mice
by Miriam Corrado, Carmine Giorgio, Elisabetta Barocelli, Giuseppe Vittucci Marzetti, Anna Maria Cantoni, Rosanna Di Lecce, Matteo Incerti, Riccardo Castelli, Alessio Lodola and Massimiliano Tognolini
Pharmaceuticals 2020, 13(4), 69; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13040069 - 16 Apr 2020
Viewed by 2578
Abstract
The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and [...] Read more.
The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and different expression of Eph receptors have been associated with tumor development and progression. In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice. The 8-week treatment with the Eph-ephrin antagonist UniPR129 significantly reduced the number of adenomas in the ileum and decreased the diameter of adenomas in the same region. Overall our data suggested as UniPR129 could be able to slow down the tumor development in APC min/J mice. These results further confirm literature data about Eph kinases as a new valuable target in the intestinal cancer and for the first time showed the feasibility of the Eph-ephrin inhibition as a useful pharmacological approach against the intestinal tumorigenesis. In conclusion this work paves the way for further studies with Eph-ephrin inhibitors in order to confirm the Eph antagonism as innovative pharmacological approach with preventive benefit in the intestinal tumor development. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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Review

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25 pages, 1077 KiB  
Review
Approaches to Manipulate Ephrin-A:EphA Forward Signaling Pathway
by Sarah Baudet, Johann Bécret and Xavier Nicol
Pharmaceuticals 2020, 13(7), 140; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13070140 - 30 Jun 2020
Cited by 8 | Viewed by 5837
Abstract
Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, [...] Read more.
Erythropoietin-producing hepatocellular carcinoma A (EphA) receptors and their ephrin-A ligands are key players of developmental events shaping the mature organism. Their expression is mostly restricted to stem cell niches in adults but is reactivated in pathological conditions including lesions in the heart, lung, or nervous system. They are also often misregulated in tumors. A wide range of molecular tools enabling the manipulation of the ephrin-A:EphA system are available, ranging from small molecules to peptides and genetically-encoded strategies. Their mechanism is either direct, targeting EphA receptors, or indirect through the modification of intracellular downstream pathways. Approaches enabling manipulation of ephrin-A:EphA forward signaling for the dissection of its signaling cascade, the investigation of its physiological roles or the development of therapeutic strategies are summarized here. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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17 pages, 860 KiB  
Review
Harnessing the Power of Eph/ephrin Biosemiotics for Theranostic Applications
by Robert M. Hughes and Jitka A.I. Virag
Pharmaceuticals 2020, 13(6), 112; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13060112 - 01 Jun 2020
Cited by 6 | Viewed by 4425
Abstract
Comprehensive basic biological knowledge of the Eph/ephrin system in the physiologic setting is needed to facilitate an understanding of its role and the effects of pathological processes on its activity, thereby paving the way for development of prospective therapeutic targets. To this end, [...] Read more.
Comprehensive basic biological knowledge of the Eph/ephrin system in the physiologic setting is needed to facilitate an understanding of its role and the effects of pathological processes on its activity, thereby paving the way for development of prospective therapeutic targets. To this end, this review briefly addresses what is currently known and being investigated in order to highlight the gaps and possible avenues for further investigation to capitalize on their diverse potential. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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14 pages, 468 KiB  
Review
Antibody Targeting of Eph Receptors in Cancer
by Peter W. Janes, Mary E. Vail, Hui K. Gan and Andrew M. Scott
Pharmaceuticals 2020, 13(5), 88; https://0-doi-org.brum.beds.ac.uk/10.3390/ph13050088 - 08 May 2020
Cited by 25 | Viewed by 6346
Abstract
The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with [...] Read more.
The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with tumor initiation, angiogenesis and metastasis. Eph receptors are thus attractive therapeutic targets, and monoclonal antibodies have been commonly developed and tested for anti-cancer activity in preclinical models, and in some cases in the clinic. This review summarizes 20 years of research on various antibody-based approaches to target Eph receptors in tumors and the tumor microenvironment, including their mode of action, tumor specificity, and efficacy in pre-clinical and clinical testing. Full article
(This article belongs to the Special Issue Targeting the Eph–ephrin System)
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