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Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3

An important drawback in the management of glioblastoma (GBM) patients is the frequent relapse upon surgery and therapy. A likely explanation is that conventional therapies poorly affect a small population of stem-like cancer cells (glioblastoma stem cells, GSCs) that remain capable of repopulating...

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Autores principales: Esposito, Carla Lucia, Nuzzo, Silvia, Ibba, Maria Luigia, Ricci-Vitiani, Lucia, Pallini, Roberto, Condorelli, Gerolama, Catuogno, Silvia, de Franciscis, Vittorio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352497/
https://www.ncbi.nlm.nih.gov/pubmed/32486489
http://dx.doi.org/10.3390/cancers12061434
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author Esposito, Carla Lucia
Nuzzo, Silvia
Ibba, Maria Luigia
Ricci-Vitiani, Lucia
Pallini, Roberto
Condorelli, Gerolama
Catuogno, Silvia
de Franciscis, Vittorio
author_facet Esposito, Carla Lucia
Nuzzo, Silvia
Ibba, Maria Luigia
Ricci-Vitiani, Lucia
Pallini, Roberto
Condorelli, Gerolama
Catuogno, Silvia
de Franciscis, Vittorio
author_sort Esposito, Carla Lucia
collection PubMed
description An important drawback in the management of glioblastoma (GBM) patients is the frequent relapse upon surgery and therapy. A likely explanation is that conventional therapies poorly affect a small population of stem-like cancer cells (glioblastoma stem cells, GSCs) that remain capable of repopulating the tumour mass. Indeed, the development of therapeutic strategies able to hit GSCs while reducing the tumour burden has become an important challenge to increase a patient’s survival. The signal transducer and activator of transcription-3 (STAT3) has been reported to play a pivotal role in maintaining the tumour initiating capacity of the GSC population. Therefore, in order to impair the renewal and propagation of the PDGFRβ-expressing GSC population, here we took advantage of the aptamer–siRNA chimera (AsiC), named Gint4.T-STAT3, that we previously have shown to efficiently antagonize STAT3 in subcutaneous PDGFRβ-positive GBM xenografts. We demonstrate that the aptamer conjugate is able to effectively and specifically prevent patient-derived GSC function and expansion. Moreover, because of the therapeutic potential of using miR-10b inhibitors and of the broad expression of the Axl receptor in GBM, we used the GL21.T anti-Axl aptamer as the targeting moiety for anti-miR-10b, showing that, in combination with the STAT3 AsiC, the aptamer–miR-10b antagonist treatment further enhances the inhibition of GSC sphere formation. Our results highlight the potential to use a combined approach with targeted RNA therapeutics to inhibit GBM tumour dissemination and relapse.
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spelling pubmed-73524972020-07-15 Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3 Esposito, Carla Lucia Nuzzo, Silvia Ibba, Maria Luigia Ricci-Vitiani, Lucia Pallini, Roberto Condorelli, Gerolama Catuogno, Silvia de Franciscis, Vittorio Cancers (Basel) Article An important drawback in the management of glioblastoma (GBM) patients is the frequent relapse upon surgery and therapy. A likely explanation is that conventional therapies poorly affect a small population of stem-like cancer cells (glioblastoma stem cells, GSCs) that remain capable of repopulating the tumour mass. Indeed, the development of therapeutic strategies able to hit GSCs while reducing the tumour burden has become an important challenge to increase a patient’s survival. The signal transducer and activator of transcription-3 (STAT3) has been reported to play a pivotal role in maintaining the tumour initiating capacity of the GSC population. Therefore, in order to impair the renewal and propagation of the PDGFRβ-expressing GSC population, here we took advantage of the aptamer–siRNA chimera (AsiC), named Gint4.T-STAT3, that we previously have shown to efficiently antagonize STAT3 in subcutaneous PDGFRβ-positive GBM xenografts. We demonstrate that the aptamer conjugate is able to effectively and specifically prevent patient-derived GSC function and expansion. Moreover, because of the therapeutic potential of using miR-10b inhibitors and of the broad expression of the Axl receptor in GBM, we used the GL21.T anti-Axl aptamer as the targeting moiety for anti-miR-10b, showing that, in combination with the STAT3 AsiC, the aptamer–miR-10b antagonist treatment further enhances the inhibition of GSC sphere formation. Our results highlight the potential to use a combined approach with targeted RNA therapeutics to inhibit GBM tumour dissemination and relapse. MDPI 2020-05-31 /pmc/articles/PMC7352497/ /pubmed/32486489 http://dx.doi.org/10.3390/cancers12061434 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Esposito, Carla Lucia
Nuzzo, Silvia
Ibba, Maria Luigia
Ricci-Vitiani, Lucia
Pallini, Roberto
Condorelli, Gerolama
Catuogno, Silvia
de Franciscis, Vittorio
Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
title Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
title_full Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
title_fullStr Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
title_full_unstemmed Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
title_short Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
title_sort combined targeting of glioblastoma stem-like cells by neutralizing rna-bio-drugs for stat3
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7352497/
https://www.ncbi.nlm.nih.gov/pubmed/32486489
http://dx.doi.org/10.3390/cancers12061434
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