Cancer Gene Therapy: The New Targeting Challenge

Abstract

Cancer is characterized by genetic alterations due, for instance, to mutations in genomic DNA caused by chemicals (mutagens such as pollutants or nitrosamines, and polycyclic aromatic hydrocarbons), radiations (e.g., prolonged exposure to ultraviolet radiation from the sun, which can lead to melanoma or other skin malignancies), and viral infections (e.g., papilloma virus; human T-cell leukemia viruses 1, 2, 3, and 4; and herpes simplex virus). Mutations in genes involved in cell proliferation, tumor suppressor genes, or proto-oncogenes may lead to uncontrolled cell proliferation into a tumor. Currently, the most widely used treatments for cancer are combinations of surgery, radiotherapy and chemotherapy. However, the effectiveness of these treatments is variable. Consequently, means of potentiating conventional treatments, as well as new strategies, need to be developed. Gene therapy is generally perceived as a treatment for rare genetic diseases, in which replacing the deficient gene by its normal counterpart has proved successful, most notably in severe combined immunodeficiency (SCID) (Fischer et al., 2010), adrenoleukodystrophy (Cartier et al., 2009), and s-thalassemia (Cavazzana-Calvo et al., 2010). However, cancer is the main focus of basic and clinical research on gene therapy (http:// www.wiley.com//legacy/wileychi/genmed/clinical/). Variable levels of success have been achieved using a broad range of genes encoding tumor suppressor proteins such as p53, antiangiogenic proteins such as anti-vascular endothelial growth factor (VEGF), inflammatory cytokines, and other proteins (Lane et al., 2010), (Candolfi et al., 2010), (Adachi et al., 2010). One of the main hurdles in gene therapy is selective delivery of recombinant vectors to the target tissue. In cancer gene therapy, administration of the vector within the tumor may be of interest, but some tumors are not readily accessible and vector dissemination to healthy cells cannot be ruled out. Today, accurate tumor targeting is a major goal of cancer gene therapy. In this chapter, we will focus on the methods developed to improve targeting in cancer gene therapy, most notably gene-directed enzyme prodrug therapy (GDEPT), which is a major focus of research at our laboratory.