Gene therapy for high-grade glioma: current approaches and future directions

Abstract

The treatment of high-grade gliomas remains difficult despite recent advances in surgery, radiotherapy and chemotherapy. True advances may emerge from the increasing understanding in molecular biology and discovery of novel mechanisms for the delivery of tumoricidal agents. In an attempt to overcome this formidable neoplasm, molecular approaches using gene therapy have been investigated clinically since 1992. The clinical trials have mainly been classified into three approaches: suicide gene therapy, immune gene therapy and oncolytic viral therapy. In this article, we review these approaches, which have been studied in previous and ongoing clinical trials.

Figure 1

HSV-tk/GCV Suicide gene therapy. In tumor cells transduced with the HSV-tk gene, HSV-tk monophosphorylates the nucleoside analog GCV that is administered systemically. The monophosphorylated GCV is then converted to triphosphate GCV in the host cells. The triphosphate form is incorporated into the DNA, and it consequently blocks DNA replication and induced apoptosis (A). The toxic triphosphate is eventually transported to neighboring cells, and provides “bystander effects” (B) leading to apoptosis (C).

Figure 2

Mechanisms of liposome-mediated IFNβ gene therapy. Histology and cDNA expression microarray analyses revealed significant inductions in apoptosis (A) and antitumor immunoresponse (B), and inhibition of neovascularization (C).

Figure 3

Oncolytic therapy. Oncolytic viral therapy utilizes replication-competent viruses which ideally can infect and replicate in tumor cells (A). The viruses specifically lyse tumor cells (B) and sequentially infect neighboring cells (C).