Combined Targeting of Glioblastoma Stem-Like Cells by Neutralizing RNA-Bio-Drugs for STAT3
Open Access
- 30 May 2020
- Vol. 12 (6), 1434
- https://doi.org/10.3390/cancers12061434
Abstract
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.Funding Information
- Associazione Italiana per la Ricerca sul Cancro (14046, 18473, 9980)
- Ministero della Salute (GR-2011-02352546)
- Regione Campania (POR Campania FESR 2014-2020 “SATIN”)
This publication has 57 references indexed in Scilit:
- Hitting a Moving Target: Glioma Stem Cells Demand New Approaches in Glioblastoma TherapyCurrent Cancer Drug Targets, 2017
- The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summaryActa Neuropathologica, 2016
- Therapeutic potential of targeting micro RNA ‐10b in established intracranial glioblastoma: first steps toward the clinicEMBO Molecular Medicine, 2016
- Cancer stem cells in glioblastomaGenes & Development, 2015
- A restricted cell population propagates glioblastoma growth after chemotherapyNature, 2012
- The transcriptional network for mesenchymal transformation of brain tumoursNature, 2009
- Glioma Stem Cell Lines Expanded in Adherent Culture Have Tumor-Specific Phenotypes and Are Suitable for Chemical and Genetic ScreensCell Stem Cell, 2009
- Glioma stem cells promote radioresistance by preferential activation of the DNA damage responseNature, 2006
- Chemotherapy resistance of glioblastoma stem cellsCell Death & Differentiation, 2006
- Essential role of STAT3 for embryonic stem cell pluripotencyProceedings of the National Academy of Sciences of the United States of America, 1999