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Targeting Ephrin Receptor Tyrosine Kinase A2 with a Selective Aptamer for Glioblastoma Stem Cells
Alessandra Affinito1, Cristina Quintavalle2, Carla Lucia Esposito3
1Department of Molecular Medicine and Medical Biotechnology, "Federico II" University of Naples, Via Tommaso de Amicis 95, 80131 Naples, Italy; Percuros B.V., Enschede, the Netherlands.
Abstract:
Despite the benefits associated with radiotherapy and chemotherapy for glioblastoma (GBM) treatment, most patients experience a relapse following initial therapy. Recurrent or progressive GBM usually does not respond anymore to standard therapy, and this is associated with poor patient outcome. GBM stem cells (GSCs) are a subset of cells resistant to radiotherapy and chemotherapy and play a role in tumor recurrence. The targeting of GSCs and the identification of novel markers are crucial issues in the development of innovative strategies for GBM eradication. By differential cell SELEX (systematic evolution of ligands by exponential enrichment), we have recently described two RNA aptamers, that is, the 40L sequence and its truncated form A40s, able to bind the cell surface of human GSCs. Both aptamers were selective for stem-like growing GBM cells and are rapidly internalized into target cells. In this study, we demonstrate that their binding to cells is mediated by direct recognition of the ephrin type-A receptor 2 (EphA2). Functionally, the two aptamers were able to inhibit cell growth, stemness, and migration of GSCs. Furthermore, A40s was able to cross the blood-brain barrier (BBB) and was stable in serum in in vitro experiments. These results suggest that 40L and A40s represent innovative potential therapeutic tools for GBM.
Insights
New RNA aptamers, 40L and A40s, target glioblastoma stem cells (GSCs) by binding EphA2. These aptamers inhibit GSC growth, stemness, and migration, with A40s crossing the blood-brain barrier, offering potential new glioblastoma therapies.
Area of Science:
- Oncology
- Biotechnology
- Molecular Biology
Background:
- Glioblastoma (GBM) often relapses after standard radiotherapy and chemotherapy.
- Glioblastoma stem cells (GSCs) are resistant to conventional treatments and drive tumor recurrence.
- Targeting GSCs and identifying new markers are critical for effective GBM treatment strategies.
Purpose of the Study:
- To identify and characterize novel RNA aptamers targeting GSCs.
- To investigate the therapeutic potential of these aptamers against GBM.
Main Methods:
- Differential cell SELEX was used to discover RNA aptamers 40L and A40s.
- Aptamer binding specificity was confirmed through EphA2 receptor recognition.
- In vitro experiments assessed aptamer effects on GSC growth, stemness, migration, and blood-brain barrier (BBB) penetration.
Main Results:
- RNA aptamers 40L and A40s selectively bind to the surface of human GSCs.
- These aptamers are internalized into GSCs and bind to the EphA2 receptor.
- Both aptamers inhibited GSC growth, stemness, and migration.
- A40s demonstrated BBB crossing ability and serum stability in vitro.
Conclusions:
- 40L and A40s aptamers represent promising novel therapeutic agents for glioblastoma.
- Targeting EphA2 on GSCs offers a potential strategy for overcoming GBM recurrence and resistance.
