Gene Therapies for Cancer: Strategies, Challenges and Successes

Gene therapy in a global context involves correction of a genetic defect by introducing a normal version of a defective or missing gene thereby correcting an underlying disorder (Friedmann, 1992). Milestones on the path of developing gene therapies are presented in Figure 1. This concept was first advanced in the 1960s after observing that viruses could cause malignant transformation in cells by integrating their genetic information into the genomes of infected cells. In 1966, Edward Tatum proposed the use of viruses in the genetic manipulation of somatic cells and its possible therapeutic applications (Tatum, 1966). A few years later, initial proof-of-concept for gene therapy was demonstrated using tobacco mosaic virus as a vector to introduce a polyadenylate stretch to viral RNA (Rogers and Pfuderer, 1968). Encouraged by these results, gene therapy was attempted in the 1970s to correct a urea cycle disorder by administering wild type Shope papilloma virus, encoding the arginase gene, to two severely handicapped young girls suffering from hyperarginemia (Rogers et al., 1973; Terheggen et al., 1975). Unfortunately, the desired outcome was not achieved. The first successful therapeutic application of this gene therapy approach was evident in 1990 when a retrovirus-vector was used to mediate transfer of the gene encoding adenosine deaminase (ADA) into the T-cells of two children suffering from severe combined immunodeficiency (SCID) (Rosenberg et al., 1990). The response was positive for only one of the patients; however, debate arose since the patient simultaneously received enzyme replacement therapy alongside gene therapy. Another study was conducted in an 18-year-old patient suffering from ornithine transcarbamylase deficiency, a relatively mild form of nitrogen metabolism disorder. However, the application of gene therapy in patients was temporarily halted following the death of a patient due to vector-associated toxicity (Stolberg, 1999). In spite of the public backlash from this incident, in the last decades a growing body of evidences supported by positive human efficacy data confirmed that gene therapy could be used to correct certain debilitating conditions including Leber’s congenital amaurosis (Maguire et al., 2009), β-thalassemia (Cavazzana-Calvo et al., 2010), X-linked severe combined immunodeficiency (SCID-X1) (Hacein-Bey-Abina et al., 2010) and cancer (Wirth et al., 2013). Additionally, an increased understanding of the genetic basis of many diseases, improvement of vectors to minimize unwanted toxicity, advances in approaches for manipulating DNA expression and delivery in a target-specific manner has raised expectations that a clinical breakthrough may be imminent. As a consequence, there have been over 1800 clinical trials already conducted or currently ongoing worldwide (Wirth et al., 2013). Fig. 1 The timelines and milestones in developing gene therapy approaches: from conception to clinical applications. Initially, gene therapy focused on rare (orphan) diseases mediated by detrimental monogenetic defects. However, with advances in the field, various chronic and progressive diseases such as heart failure, neurodegeneration or metabolic disorders were also evaluated using gene therapy approaches. These studies indicated that gene therapy techniques have broad potential applications, although cancer comprises over 60% of all ongoing clinical gene trials (Wirth et al., 2013). In this review, we focus on various gene therapy strategies that are currently employed, roadblocks and challenges in the field of cancer gene therapy, and a brief discussion of a few current successful applications of gene therapy for cancer.