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Biomedicines
Volume 14
Issue 9
10.3390/biomedicines14092010
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Addressing the Limits of Emx2 Therapy of Glioblastoma Multiforme by Transgene Insulation and Epigenetic Pharmacological Intervention

by
Mariacarmine Tuccillo
1,2,
Olga Pastorino
1,3,
Carmen Falcone
1,4,
Jessica Zucco
1,5,
Giampiero Leanza
6,7 and
Antonello Mallamaci
1,*
1
Department of Neuroscience, Scuola Internazionale Superiore di Studi Avanzati (SISSA), Via Bonomea 265, 34136 Trieste, Italy
2
Present Affiliation: Telethon Institute of Genetics and Medicine (TIGEM), 80078 Pozzuoli, Italy
3
Present Affiliation: Independent Researcher, 34136 Trieste, Italy
4
Present Affiliation: Department of Biological Sciences, Towson University, 8000 York Road, Towson, MD 21252, USA
5
Present Affiliation: Institute of Medical Genetics, University Hospital ‘Santa Maria della Misericordia’, Azienda Sanitaria Universitaria Friuli Centrale (ASUFC), Piazzale Santa Maria della Misericordia, 15, 33100 Udine, Italy
6
Department of Life Sciences, University of Trieste, Via Fleming 22, 34127 Trieste, Italy
7
Present Affiliation: Department of Drug and Health Sciences, University of Catania, Viale A. Doria 6 (Bldg 2), 95125 Catania, Italy
*
Author to whom correspondence should be addressed.
Biomedicines 2026, 14(9), 2010; https://doi.org/10.3390/biomedicines14092010
Submission received: 19 July 2026 / Revised: 21 August 2026 / Accepted: 24 August 2026 / Published: 7 September 2026
(This article belongs to the Special Issue Cell Metabolism in Brain Physiology and Pathology: From Molecular Mechanisms to Therapeutic Targets)
Review Reports Versions Notes

Abstract

Introduction/Objectives: Implicated in the regionalization of the anterior central nervous system (CNS) and the progression of pallial astrogliogenesis, the transcription factor gene EMX2 has been reported to be specifically silenced in several tumors, both non-neural and neural. Based on that, its overexpression has been proposed as a tool for the treatment of a subset of these malignancies, including glioblastoma. Here we tested this proposal. Methods/Results: We found that Emx2 overexpression in human glioblastoma cells transplanted into the striatum of immunotolerant mice significantly prolonged animals’ survival, outperforming their treatment by temozolomide. However, this approach did not eradicate the tumor, because of in vivo silencing of the therapeutic Emx2 transgene. Notably, silencing of this transgene (or of a reporter designed to monitor its competence to be expressed) also occurred during long-term in vitro culture of GBM cells and was exacerbated by coculture with murine pallial glia under hypoxic conditions. Remarkably, partial insulation of the transgene and the use of a specific combination of epigenetic drugs substantially counteracted the progressive activatability decline undergone by the Emx2-transgene expression reporter, suggesting a promising strategy for overcoming a major limitation of Emx2-based therapy for GBM. Conclusions: An Emx2-encoding transgene, protected by insulation and appropriate epigenetic drugs, can provide a substantial benefit in experimental therapy for glioblastoma.
Keywords: Emx2; glioblastoma; gene therapy; gene silencing; gene insulation Emx2; glioblastoma; gene therapy; gene silencing; gene insulation

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MDPI and ACS Style

Tuccillo, M.; Pastorino, O.; Falcone, C.; Zucco, J.; Leanza, G.; Mallamaci, A. Addressing the Limits of Emx2 Therapy of Glioblastoma Multiforme by Transgene Insulation and Epigenetic Pharmacological Intervention. Biomedicines 2026, 14, 2010. https://doi.org/10.3390/biomedicines14092010

AMA Style

Tuccillo M, Pastorino O, Falcone C, Zucco J, Leanza G, Mallamaci A. Addressing the Limits of Emx2 Therapy of Glioblastoma Multiforme by Transgene Insulation and Epigenetic Pharmacological Intervention. Biomedicines. 2026; 14(9):2010. https://doi.org/10.3390/biomedicines14092010

Chicago/Turabian Style

Tuccillo, Mariacarmine, Olga Pastorino, Carmen Falcone, Jessica Zucco, Giampiero Leanza, and Antonello Mallamaci. 2026. "Addressing the Limits of Emx2 Therapy of Glioblastoma Multiforme by Transgene Insulation and Epigenetic Pharmacological Intervention" Biomedicines 14, no. 9: 2010. https://doi.org/10.3390/biomedicines14092010

APA Style

Tuccillo, M., Pastorino, O., Falcone, C., Zucco, J., Leanza, G., & Mallamaci, A. (2026). Addressing the Limits of Emx2 Therapy of Glioblastoma Multiforme by Transgene Insulation and Epigenetic Pharmacological Intervention. Biomedicines, 14(9), 2010. https://doi.org/10.3390/biomedicines14092010

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