Gene therapy for malignant glioma - PubMed (original) (raw)

Review

Gene therapy for malignant glioma

Hidehiro Okura et al. Mol Cell Ther. 2014.

Abstract

Glioblastoma multiforme (GBM) is the most frequent and devastating primary brain tumor in adults. Despite current treatment modalities, such as surgical resection followed by chemotherapy and radiotherapy, only modest improvements in median survival have been achieved. Frequent recurrence and invasiveness of GBM are likely due to the resistance of glioma stem cells to conventional treatments; therefore, novel alternative treatment strategies are desperately needed. Recent advancements in molecular biology and gene technology have provided attractive novel treatment possibilities for patients with GBM. Gene therapy is defined as a technology that aims to modify the genetic complement of cells to obtain therapeutic benefit. To date, gene therapy for the treatment of GBM has demonstrated anti-tumor efficacy in pre-clinical studies and promising safety profiles in clinical studies. However, while this approach is obviously promising, concerns still exist regarding issues associated with transduction efficiency, viral delivery, the pathologic response of the brain, and treatment efficacy. Tumor development and progression involve alterations in a wide spectrum of genes, therefore a variety of gene therapy approaches for GBM have been proposed. Improved viral vectors are being evaluated, and the potential use of gene therapy alone or in synergy with other treatments against GBM are being studied. In this review, we will discuss the most commonly studied gene therapy approaches for the treatment of GBM in preclinical and clinical studies including: prodrug/suicide gene therapy; oncolytic gene therapy; cytokine mediated gene therapy; and tumor suppressor gene therapy. In addition, we review the principles and mechanisms of current gene therapy strategies as well as advantages and disadvantages of each.

Keywords: Cytokine mediated; Gene therapy; Glioblastoma; Oncolytic; Prodrug suicide; Tumor suppressor gene.

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Figures

Figure 1

Figure 1

Strategy for suicide gene therapy. The aim of suicide gene therapy strategy is to increase the delivery of toxic metabolites to tumor cells and result in efficient cell death. Initially, a gene encoding a prodrug-activating enzyme is delivered by a tumor-targetting viral vector. Subsequent systemic administration of an inactive prodrug results in generation of a toxic metabolite and cell death of the transduced cells and non-trasduced bystander tumor cells (bystander effect) only at the tumor site.

Figure 2

Figure 2

Strategy and mechanism for oncolytic gene therapy. (A); Oncolytic gene therapy employs replication-competent virus vectors capable of selective replication in target tumor cells. Spreading to new adjacent progeny cells occurs as the host cell is lysed and progeny virus is released. (B); Most viruses can replicate poorly in normal cells by a defense mechanism as follows. In response to viral infection, Protein Kinase R (PKR) in the host cells shut off protein synthesis by which PKR dimerizes and is inactivated by autophosphorylation resulting in the conversion of eukaryotic initiation factor-2 alpha (EIF-2α) into its inactive state following phosphorylation, which is required for translation initiation. Consequently, translation is arrested in the infected host cells as an anti-viral protective mechanism. However, the ICP34.5 in HSV-1 can overcome this defense by recruiting protein phosphatase-1α to dephosphorylate EIF-2α allowing protein synthesis to proceed. Therefore, when a deletion of γ34.5 gene is engineered, the HSV-1 mutant can no longer successfully proliferate in non-replicating cells. HSV-1 lacking ICP34.5 activity can only infect cells with defective PKR pathway. In tumor cells, PKR autophosphorylation is blocked due to Ras activation, permitting replication of viruses lacking the γ34.5 gene in tumor cells with hyper-activated Ras.

Figure 3

Figure 3

Strategy of cytokine mediated gene therapy. Cytokine mediated gene therapy involves tumor-selective gene transfer and in situ expression of various cytokine genes such as interleukin (IL) and interferon (IFN) capable of attracting immunocompetent cells such as macrophages (MΦ), natural killer cells (NK), and cytotoxic T lymphocytes (CTL) inducing immune response.

Figure 4

Figure 4

Strategy of tumor suppressor gene therapy. Tumor suppressor gene therapy aims to reprogram tumor cells by restoring the function of a tumor suppressor gene lost or functionally inactivated in cancer cells, subsequently inducing cell cycle arrest or apoptosis.

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