Abstract
Glioblastoma (GBM) has the worst prognosis among brain tumors, hence basic biology, preclinical, and clinical studies are necessary to design effective strategies to defeat this disease. Gene transfer vectors derived from the most-studied lentivirus—the Human Immunodeficiency Virus type 1—have wide application in dissecting GBM specific features to identify potential therapeutic targets. Last-generation lentiviruses (LV), highly improved in safety profile and gene transfer capacity, are also largely employed as delivery systems of therapeutic molecules to be employed in gene therapy (GT) approaches. LV were initially used in GT protocols aimed at the expression of suicide factors to induce GBM cell death. Subsequently, LV were adopted to either express small noncoding RNAs to affect different aspects of GBM biology or to overcome the resistance to both chemo- and radiotherapy that easily develop in this tumor after initial therapy. Newer frontiers include adoption of LV for engineering T cells to express chimeric antigen receptors recognizing specific GBM antigens, or for transducing specific cell types that, due to their biological properties, can function as carriers of therapeutic molecules to the cancer mass. Finally, LV allow the setting up of improved animal models crucial for the validation of GBM specific therapies.
Highlights
Glioblastoma (GBM) is the most aggressive brain tumor, with poor prognosis and scarce progression-free survival time, usually leading to death within 20 months after initial diagnosis [1].Currently, GBM classification by the World Health Organization couples clinical features to molecular phenotype, distinguishing isocitrate dehydrogenase (IDH) wildtype GBMs, mostly primary developed tumors accounting for nearly 90% of cases, from IDH mutant GBMs, usually arising as secondary tumors from lower grade gliomas and otherwise not specified GBMs [2]
LV offer several advantages over different viral and nonviral gene delivery vehicles: (i) the ability of transducing both dividing and resting cells; (ii) high efficiency in delivering transgenes to primary and stem cells; (iii) the capability of integrating their genome into the host DNA, leading to a sustained transgene expression; in addition, as mentioned above, LV show a potentially safer integration site profile when compared to gammaretroviral vectors [8]; (iv) a tissue tropism that can be modified by providing the viral core particles with an heterologous glycoprotein envelope
MiR-297 was unraveled as a factor promoting survival of GBM cells, by targeting diacylglycerol kinase alpha [47]. Considering their crucial roles in tumor biology and their peculiar transcriptional signature in cancer cells, miRNAs have been considered a suitable target for developing novel therapeutic strategies to fight GBM
Summary
Glioblastoma (GBM) is the most aggressive brain tumor, with poor prognosis and scarce progression-free survival time, usually leading to death within 20 months after initial diagnosis [1]. (iii) the capability of integrating their genome into the host DNA, leading to a sustained transgene expression; in addition, as mentioned above, LV show a potentially safer integration site profile when compared to gammaretroviral vectors [8]; (iv) a tissue tropism that can be modified by providing the viral core particles with an heterologous glycoprotein envelope This process, known as pseudotyping, can be exploited to extend the natural tropism of the parental virus, which otherwise would be restricted to CD4 positive T cells and/or to allow an efficient and possibly specific targeting of cell types of interest. Thanks to the developed platform, those authors were able to demonstrate that local DNA sequence and regional chromatin affect regulatory activity, further advancing our vision of noncoding genome in GBM development [31]
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