Glioblastoma – Can Gene Therapy Really Help?by Viatcheslav Wlassoff, PhD | June 14, 2016
Glioblastoma is one of the deadliest tumours, with very low survival rate and no efficient therapies available. The current gold standards of management, namely surgery, chemo- and radiotherapy, have little effectiveness since these tumours typically exhibit very aggressive recurrences within a short time frame. In spite of concerted international efforts over the past few decades, an effective treatment for these tumours has remained elusive.
It is sad but true that a diagnosis of glioblastoma is almost equivalent to a death sentence, and most patients who have been diagnosed with a WHO grade IV malignant glioma survive only about 12 months. Although new molecular pathways involved in glioblastoma invasiveness are constantly being uncovered, translation of basic science research into clinical applications has been slow. Additionally, despite advances in treatments contributing to small improvements in survival of patients with glioblastomas, much more needs to be done before the number of positive outcomes can increase significantly to the extent that we often see in other types of cancers which can be now successfully treated.
A gene which could be directly involved in finding a glioblastoma treatment
Scientists from Italy recently reported promising results which demonstrated that the technique of gene therapy could potentially give hope in the fight against glioblastomas. In this study, the team focused on introducing an additional copy of a specific gene into the tumour cells. What is remarkable here is that this would then, in turn, lead to subsequent impairment of the reproductive capacity of these cells and eventually result in cellular suicide.
Notably, the inspiration that sparked this study came about after years of study on one gene called Emx2. A key characteristic of this gene is that it is able to work during embryonic growth to inhibit astrocyte proliferation. Astrocytes are a type of glial cell which form part of the nervous system, and they function to regulate neuronal function in conjunction with conferring protective effects and nourishment for neurons.
To date, it is well-known that only neurons grow in early stages of nervous system development, while the proliferation of glial cells only occurs at the point when the growth of neurons is almost completed. Previous studies reported that in the early phase of neuronal generation, Emx2 was expressed at extremely high levels, while it was observed that this action decreases drastically upon the initiation of glial cell growth. As such, this suggests the Emx2 is a gene which is able to intrinsically check astrocyte growth up to a specific point.
The next question the researchers asked was that if this gene can inhibit the growth of astrocytes, wouldn’t it be a good idea to draw a parallel and use it to target and treat glioblastomas? This concept largely stemmed from the fact that glioblastomas are tumours which share many common features with astroglia. Hence, the scientists decided to use this to their advantage. To this end, they started gathering cultures of a variety of glioblastoma types and performed tests on them to determine the effects of Emx2 on glioblastoma. Amazingly, the tumour tissue collapsed in less than one week in almost all the samples used, indicating the important role this gene could play in blocking glioblastomas.
From here, the study proceeded in two directions. Firstly, the scientists used an in vitro system to model the molecular mechanisms which intervene between two points, namely when the presumed gene with therapeutic effects is turned on, and the final desired effect. In corroboration with their previous findings, it was shown that this gene indeed attacked tumour metabolism at a minimum of at least six points, further implying the possibility of its relevance for brain tumour treatment.
The following step after the in vitro experiments involved the team embarking on its pioneering in vivo work on mice. In order to prevent damage to healthy neurons, astrocytes and cells, the scientists first identified a specific fragment of DNA known as a promotor for the target gene to perform their study. Specifically, the use of the promotor caused the therapeutic Emx2 gene to become selectively activated in only the tumour cells without any damage to other healthy cells.
Indeed, the results robustly reproduced the phenotype shown in the initial in vitro tests, supporting the earlier findings.
Promising results from gene therapy: a future cure on the horizon?
The fundamental principle of gene therapy is that it is based on inserting genes into the genome of a host cell so that the genes of interest are able to function inside the cell through using the cell’s intrinsic genetic machinery. The logical question to ask is then how the portion of the genetic code can be injected into a living cell?
Scientists have learnt to make use of naturally adopted mechanisms by viruses to achieve this. The key fact about viruses is that although viruses possess their own genome, they cannot self-duplicate and reproduce without external help. As such, viruses enter cells and insert their DNA into the host cell’s genome. The cell will then work for the virus via duplicating the viral genes and this leads to the formation of other viruses.
Importantly, new genes or enhanced forms of endogenous genes can be added to the whole cell if the virus is made harmless and “inserted” with therapeutic genes. Using this approach, the scientists introduced an exceptionally active form of Emx2 into the tumour cells via viral vectors. The results from this experiment were extremely promising: Emx2 was shown to be able to kill at least four types of glioblastoma cells without harming healthy cells in the nervous system.
Moreover, since the treatment targeted multiple points of tumour metabolism, there is a higher statistical probability of preventing aggressive recurrences via elevating the current standards in the selection process. To this end, the hope is that the in vivo tests can be extended to other types of glioblastomas and be applied from the bench to the bedside in the years to come.
Falcone, C., Daga, A., Leanza, G., & Mallamaci, A. (2014). Emx2 as a novel tool to suppress glioblastoma Oncotarget DOI: 10.18632/oncotarget.9322
Omuro, A. (2013). Glioblastoma and Other Malignant Gliomas JAMA, 310 (17) DOI: 10.1001/jama.2013.280319
Seymour, T., Nowak, A., & Kakulas, F. (2015). Targeting Aggressive Cancer Stem Cells in Glioblastoma Frontiers in Oncology, 5 DOI: 10.3389/fonc.2015.00159
Veliz I, Loo Y, Castillo O, Karachaliou N, Nigro O, & Rosell R (2015). Advances and challenges in the molecular biology and treatment of glioblastoma-is there any hope for the future? Annals of translational medicine, 3 (1) PMID: 25705639
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