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Multireceptor targeting of glioblastoma

BACKGROUND: Treatment for glioblastoma (GBM) remains an unmet need in medicine. Novel therapies that address GBM complexity and heterogeneity in particular are warranted. To this end, we target 4 tumor-associated receptors at a time that span virtually all of the GBM microenvironment including bulk...

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Autores principales: Sharma, Puja, Sonawane, Poonam, Herpai, Denise, D’Agostino, Ralph, Rossmeisl, John, Tatter, Stephen, Debinski, Waldemar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596893/
https://www.ncbi.nlm.nih.gov/pubmed/33150335
http://dx.doi.org/10.1093/noajnl/vdaa107
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author Sharma, Puja
Sonawane, Poonam
Herpai, Denise
D’Agostino, Ralph
Rossmeisl, John
Tatter, Stephen
Debinski, Waldemar
author_facet Sharma, Puja
Sonawane, Poonam
Herpai, Denise
D’Agostino, Ralph
Rossmeisl, John
Tatter, Stephen
Debinski, Waldemar
author_sort Sharma, Puja
collection PubMed
description BACKGROUND: Treatment for glioblastoma (GBM) remains an unmet need in medicine. Novel therapies that address GBM complexity and heterogeneity in particular are warranted. To this end, we target 4 tumor-associated receptors at a time that span virtually all of the GBM microenvironment including bulk tumor cells, infiltrating tumor cells, neovasculature, and tumor-infiltrating cells with one pharmaceutical agent delivering a cytotoxic load. METHODS: We engineered multivalent ligand-based vector proteins termed QUAD with an ability to bind to 4 of the following GBM-associated receptors: IL-13RA2, EphA2, EphA3, and EphB2. We conjugated QUAD with a modified bacterial toxin PE38QQR and tested it in vitro and in vivo. RESULTS: The QUAD variants preserved functional characteristics of the respective ligands for the 4 receptors. The QUAD 3.0 variant conjugate was highly cytotoxic to GBM cells, but it was nontoxic in mice, and the conjugate exhibited strong antitumor effect in a dog with spontaneous GBM. CONCLUSION: The QUAD addresses, to a large extent, the issues of intra- and intertumoral heterogeneity and, at the same time, it targets several pathophysiologically important tumor compartments in GBM through multiple receptors overexpressed in tumors allowing for what we call “molecular resection.” QUAD-based targeted agents warrant further pre- and clinical development.
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spelling pubmed-75968932020-11-03 Multireceptor targeting of glioblastoma Sharma, Puja Sonawane, Poonam Herpai, Denise D’Agostino, Ralph Rossmeisl, John Tatter, Stephen Debinski, Waldemar Neurooncol Adv Basic and Translational Investigations BACKGROUND: Treatment for glioblastoma (GBM) remains an unmet need in medicine. Novel therapies that address GBM complexity and heterogeneity in particular are warranted. To this end, we target 4 tumor-associated receptors at a time that span virtually all of the GBM microenvironment including bulk tumor cells, infiltrating tumor cells, neovasculature, and tumor-infiltrating cells with one pharmaceutical agent delivering a cytotoxic load. METHODS: We engineered multivalent ligand-based vector proteins termed QUAD with an ability to bind to 4 of the following GBM-associated receptors: IL-13RA2, EphA2, EphA3, and EphB2. We conjugated QUAD with a modified bacterial toxin PE38QQR and tested it in vitro and in vivo. RESULTS: The QUAD variants preserved functional characteristics of the respective ligands for the 4 receptors. The QUAD 3.0 variant conjugate was highly cytotoxic to GBM cells, but it was nontoxic in mice, and the conjugate exhibited strong antitumor effect in a dog with spontaneous GBM. CONCLUSION: The QUAD addresses, to a large extent, the issues of intra- and intertumoral heterogeneity and, at the same time, it targets several pathophysiologically important tumor compartments in GBM through multiple receptors overexpressed in tumors allowing for what we call “molecular resection.” QUAD-based targeted agents warrant further pre- and clinical development. Oxford University Press 2020-08-26 /pmc/articles/PMC7596893/ /pubmed/33150335 http://dx.doi.org/10.1093/noajnl/vdaa107 Text en © The Author(s) 2020. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Basic and Translational Investigations
Sharma, Puja
Sonawane, Poonam
Herpai, Denise
D’Agostino, Ralph
Rossmeisl, John
Tatter, Stephen
Debinski, Waldemar
Multireceptor targeting of glioblastoma
title Multireceptor targeting of glioblastoma
title_full Multireceptor targeting of glioblastoma
title_fullStr Multireceptor targeting of glioblastoma
title_full_unstemmed Multireceptor targeting of glioblastoma
title_short Multireceptor targeting of glioblastoma
title_sort multireceptor targeting of glioblastoma
topic Basic and Translational Investigations
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596893/
https://www.ncbi.nlm.nih.gov/pubmed/33150335
http://dx.doi.org/10.1093/noajnl/vdaa107
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