Preface [HotTopic: Genomics-Based Anti-Cancer Drug Discovery (Guest Editor: Gayathri R. Devi)]

In theory, the development of genomics-based agents to inhibit gene expression is simple and straightforward. With the availability of the human genome sequence, the strategy of employing nucleic acids with sequences complementary to specific target genes has gained great importance. Manipulation of gene expression by these agents is a strategy that offers the ability to improve drug discovery and target validation. At the same time, such strategies possess the unique capability of providing corresponding therapeutic entities for various diseases, including cancer, as they offer the possibility of rational design with high specificity and relatively inexpensive cost. This issue of Current Pharmaceutical Biotechnology, in addition to providing a snapshot of the emerging strategies to inhibit gene expression and examples of drug-able molecular targets for cancer therapy, will also aim to address key issues like in vivo delivery and biodistribution, pharmacokinetics, and toxicological aspects of interfering with the gene function. Recently, drug discovery and target validation in the pharmaceutical sector has been driven largely by various genomics-based approaches. These include, but are not limited to, antisense technology, destabilization of mRNA using RNAi or ribozymes, and antigene strategies (summarized by Scanlon). The use of various model systems like zebrafish for evaluating functional genomics (reviewed by Chen and Ekker) provides the potential of greatly reducing time and cost of initial target screening and bioassay development. Siedman presents an energetic insight into the world of oligonucleotide-mediated gene targeting which includes homologous recombination, triple helix forming oligomers, and newer approaches like peptide nucleic acids, engineered zinc finger proteins, and polyamide minor groove binders. Most of the oligonucleotides that have entered clinical trials from companies like Genta, ISIS and Hybridon possess an internucleoside charge. The presence of the ionic character has been observed to be responsible for oligonucleotide binding to various proteins and also provides a reactive center for potential drug interactions. Newer chemistries like phosphorodiamidate Morpholino oligomers offer neutral entities and RNase independent mechanism of action. Arora et al. from AVI BioPharma present a critical view of the issues like tissue biodistribution, efficacy and provide pharmacokinetic data to compare Morpholinos with other ionic oligonucleotides. There is also a great deal of exuberance in the research community about RNAi technology. The concept of RNA interference (reviewed by Banan and Puri, Ambion) involves introduction of double stranded RNA into cells, which subsequently causes sequence-specific degradation of mRNA resulting in gene silencing. The fundamental concern for oligonucleotide-based therapy relies upon the capacity of the oligonucleotide to gain access to the target RNA. Kimchi-Sarfaty and Gottesman review a highly promising SV40-based vector delivery system to deliver DNA in vivo for cancer therapy. Last but not the least, this issue also provides some compelling translational applicability (reviewed by Ko and Balk) regarding targeting key receptor pathways for hormone-dependent cancers. Kumar et al. have reviewed the powerful method of regulating apoptotic / proliferation imbalance in cancer cells using genomics-based agents to overcome chemotherapeutic resistance. There is no doubt that the genomics revolution has arrived and the tools needed to derive practical therapeutic benefits are at hand, however, rapid screening systems, better delivery strategies, and understanding of toxicological parameters will ensure its staying power.