Target validation to biomarker development: focus on RNA interference.

With the growing number of putative molecular targets and increased economic pressure on companies developing novel drugs, particularly in the cancer area, the need to work on highly validated targets is essential. The use of biomarkers for proof of mechanism of action is becoming an important tool in validation efforts in the preclinical phase of drug development, helping to reduce the attrition rate of candidate drugs once they have entered the clinic. In this review, we highlight how RNA interference (RNAi) has become the method of choice to perform both target validation and identification in academia and industry. RNAi takes advantage of a naturally occurring mechanism whereby cells regulate the expression of genes at the post-transcriptional level, and it introduces a new era in loss-of-function experiments, allowing for the rapid measurement of the phenotype observed upon target expression abrogation. Design of both small-interfering RNA and short-hairpin RNA constructs and their delivery into cells have emerged as the most important aspects of this technology, and reduction or measurement of potential unwanted off-target effects must also be taken into consideration. A number of successes have already been described, and several oncology targets and biomarkers have been identified and validated with this technique.