Conclusions

The paucity of effective anticancer treatment options and our improved understanding of the molecular bases of cancer phenotypes provide compelling rationales for target-based drug development. To generate cost-effective and efficacious treatments, it is essential to exploit the best targets by the most efficient development routes using evidence-based decision making to prioritize targets and leads at an early stage and to determine appropriate clinical endpoints to identify relevant beneficial biological effects which may sometimes occur in the absence of an objective reduction of tumor volume. A large amount of evidence supports the clinical development of strategies to target telomerase, and we are now seeing the fruits of intense target validation efforts manifest in several active clinical trials. However, while some approaches are relatively advanced, development of small molecule strategies has been slow. The development paths for telomerase-directed therapeutics are diverse and in some cases will require issues such as the phenotypic lag to be addressed. Telomerase consists of a number of targets that can theoretically be exploited by the small molecule route, suggesting that there is still substantial scope for development of leads with alternative mechanisms of action. Cell-based screening could be applied to investigate most of the telomerase-related targets, hopefully improving the quality of early leads. In some cases, such as cell-based screening using the telomerase promoters, it may be possible to identify novel anticancer signal trans-duction inhibitors whose principle mode of action need not be telomerase-specific. Secondary assays and target identification approaches will need to be defined on a screen-by-screen basis, but preclinical models should include demonstration of selectivity for cancer cells and efficacy in relevant in vivo models. Concerted efforts are now required to translate laboratory findings into viable therapeutic candidates.

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