Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors

Abstract Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epi...

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Autores principales: Yanni Zhu, Nicole Bassoff, Clemens Reinshagen, Deepak Bhere, Michal O. Nowicki, Sean E. Lawler, Jérémie Roux, Khalid Shah
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Lenguaje:EN
Publicado: Nature Portfolio 2017
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Acceso en línea:https://doaj.org/article/2012dc1702134a00bc4fa931d84efa4f
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spelling oai:doaj.org-article:2012dc1702134a00bc4fa931d84efa4f2021-12-02T12:30:37ZBi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors10.1038/s41598-017-02483-92045-2322https://doaj.org/article/2012dc1702134a00bc4fa931d84efa4f2017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-02483-9https://doaj.org/toc/2045-2322Abstract Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor-mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting.Yanni ZhuNicole BassoffClemens ReinshagenDeepak BhereMichal O. NowickiSean E. LawlerJérémie RouxKhalid ShahNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017)
institution DOAJ
collection DOAJ
language EN
topic Medicine
R
Science
Q
spellingShingle Medicine
R
Science
Q
Yanni Zhu
Nicole Bassoff
Clemens Reinshagen
Deepak Bhere
Michal O. Nowicki
Sean E. Lawler
Jérémie Roux
Khalid Shah
Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors
description Abstract Developing therapeutics that target multiple receptor signaling pathways in tumors is critical as therapies targeting single specific biomarker/pathway have shown limited efficacy in patients with cancer. In this study, we extensively characterized a bi-functional molecule comprising of epidermal growth factor receptor (EGFR) targeted nanobody (ENb) and death receptor (DR) targeted ligand TRAIL (ENb-TRAIL). We show that ENb-TRAIL has therapeutic efficacy in tumor cells from different cancer types which do not respond to either EGFR antagonist or DR agonist monotherapies. Utilizing pharmacological inhibition, genetic loss of function and FRET studies, we show that ENb-TRAIL blocks EGFR signalling via the binding of ENb to EGFR which in turn induces DR5 clustering at the plasma membrane and thereby primes tumor cells to caspase-mediated apoptosis. In vivo, using a clinically relevant orthotopic resection model of primary glioblastoma and engineered stem cells (SC) expressing ENb-TRAIL, we show that the treatment with synthetic extracellular matrix (sECM) encapsulated SC-ENb-TRAIL alleviates tumor burden and significantly increases survival. This study is the first to report novel mechanistic insights into simultaneous targeting of receptor-mediated proliferation and cell death signaling pathways in different tumor types and presents a promising approach for translation into the clinical setting.
format article
author Yanni Zhu
Nicole Bassoff
Clemens Reinshagen
Deepak Bhere
Michal O. Nowicki
Sean E. Lawler
Jérémie Roux
Khalid Shah
author_facet Yanni Zhu
Nicole Bassoff
Clemens Reinshagen
Deepak Bhere
Michal O. Nowicki
Sean E. Lawler
Jérémie Roux
Khalid Shah
author_sort Yanni Zhu
title Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors
title_short Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors
title_full Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors
title_fullStr Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors
title_full_unstemmed Bi-specific molecule against EGFR and death receptors simultaneously targets proliferation and death pathways in tumors
title_sort bi-specific molecule against egfr and death receptors simultaneously targets proliferation and death pathways in tumors
publisher Nature Portfolio
publishDate 2017
url https://doaj.org/article/2012dc1702134a00bc4fa931d84efa4f
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