RNA interference-mediated validation of genes involved in telomere maintenance and evasion of apoptosis as cancer therapeutic targets.

The discovery of new cancer-related therapeutic targets is mainly based on the identification of genes involved in pathways selectively exploited in cancer cells, including those leading to unlimited replicative potential, evasion of apoptosis, angiogenesis, tissue invasion and metastatic spread. Potentially, a gene--or a gene product--is recognized as a cancer target whether its modulation in experimental models can specifically modify or revert the cancer phenotype. As soon as RNA interference (RNAi)--a natural gene silencing mechanism--was demonstrated in mammalian cells, it rapidly became an essential means for gene knockdown in preclinical models, making it possible to define the role of several human genes and to identify those specifically involved in the onset and progression of cancer. Owing to its powerful gene-silencing properties, RNAi has been proposed as a useful tool to validate new therapeutic targets and to develop innovative anticancer therapies. This chapter summarizes the findings from recent studies relying on the use of RNAi-based approaches to functionally validate therapeutic targets related to two tumor hallmarks: the unlimited replicative potential (i.e., activation of telomere maintenance mechanisms) and evasion of apoptosis (i.e., up-regulation of anti-apoptotic factors).