Editorial [Hot Topic: Gene Therapy for Cancer (Guest Editor: Maria G. Castro)]

Novel treatments for cancer will require the development of approaches, which encompass several mechanisms of action, including different modes of cell death and immune stimulation. These novel therapies would work synergistically with the best treatment options currently available. Gene-based therapies constitute a very attractive approach for cancer. There are several approaches currently being pursued; which include oncolytic viruses, which will selectively replicate in cancer cells, causing their destruction; anti-angiogenic targets which aim at depriving the growing tumor of new blood vessels needed for it to spread; targeted toxins as oncolytic molecules; immune-stimulatory targets which aim at eliciting an anti-tumor immune response which should inhibit tumor growth and also metastatic disease. Also, there are efforts directed at inhibiting signal transduction pathways, which are activated in certain cancers and which have been shown to mediate tumor progression. Although many of these approaches have shown excellent efficacy with low or no toxicity in preclinical animal models, their success has not been reproduced in human clinical trials. The reason for this can be several, such as the need to enhance the specificity and efficacy of the gene transfer vectors and the therapies. This can be achieved by the use of targeted vectors, which have been engineered so that they can only infect tumor cells, or the use of cancer cells' specific promoters which will drive the expression of therapeutic molecules exclusively in the tumor. Another important hurdle, especially with the use of oncolytic viruses, it to be able to limit the viral replication to only cancerous cells, this will also prevent untoward systemic toxicity and spread of the vectors onto other tissues throughout the body. The abiltity to generate a systemic long lived antitumor immune response is also a critical advancement which would prove very powerful for the treatment of cancers which can metastasize throughout the body, and also in the case of recurrences. Immune stimulatory approaches mediated through the delivery of genes which induce immune cell recruitment and/or activation is an approach which is being actively pursued. For the clinical implementation of these therapies, it is imperative to be able to monitor disease progression and persistence of the genetic-based therapy in vivo, using non-invasive imaging techniques. This is an exciting area of cancer gene therapy research, which is currently being actively pursued, and will enable the monitoring of the persistence of the therapeutic vectors and also their putative biodistribution. Perhaps the biggest challenge before these gene-based therapies can be sussessfully and safely implemented to treat human cancers, is the issue of the toxicity and biodistribution of the gene transfer vectors used. Also, the pre-existing immune response to the vectors can have very serious deleterious effects, not only by down-modulating the effects of the therapy by inhibiting therapeutic gene expression, but also by causing severe immune-related systemic adverse side effects. Again, this is an area which is the focus of many investigations and has led to the development of better and safer vectors. In this exciting issue, I have aimed at including reviews which span all the areas which I highlighted above, from novel therapeutic targets, to the use of safer and more efficacious gene transfer vectors, to novel non-invasive in vivo imaging approaches. I hope it will be useful to steer renewed enthusiasm to continue working in this exciting field and bring it closer to clinical success. I would like to thank Dr. Ignacio Anegon for giving me the opportunity to put together this exciting Special Issue of the journal, Dr. Pedro Lowenstein for his unfailing support for this project and all our gene therapy efforts aimed at bringing cancer therapeutics closer to the bedside. Very importantly, I wish to convey my infinite gratitude to all the authors, who with zest and enthusiasm, in spite of increasingly mounting academic pressures, took the time to prepare exciting and timely reviews in their areas of expertise. Thank you all for all your support and enjoy!