Chapter 1 - Preclinical Drug Development: Translating Basic Research into Clinical Work

Recent advances in biomedical research and the expansion of preclinical laboratory investigation have resulted in improved knowledge of the biology and genesis of cancer, and have shed relevant insights on the complex relationship between tumour cells and their microenvironment. Several signalling pathways deregulated in cancer cells have been discovered and components of these pathways that are critical for tumour genesis and progression represent targets for the development of new agents. The identification of a large number of possible targets has resulted in an even larger number of new therapeutic agents that have entered clinical evaluation, giving hope that better treatment strategies could be developed to overcome resistance of cancer cells to standard treatments and to improve patient outcomes. Unfortunately, despite the efforts of the pharmaceutical industry and academic institutions, only few new agents have shown a significant impact on survival and most patients with advanced disease remain incurable.

There are several reasons that could explain why most of the new anti-cancer agents have failed to improve treatment results. Cancer is a complex disease and several genetic changes accumulate that affect components of the same or different pathways, and render it difficult to identify a specific target that would be uniquely susceptible to pharmacological inhibition. On the other hand, many agents that have shown significant anti-tumour activity in preclinical studies have failed to reproduce these results when tested in the clinic. Preclinical studies are important because they represent the first step toward the development of a new therapeutic compound, providing important information on the mechanism of action, anti-tumour activity, pharmacology, and toxicology that can guide its subsequent clinical development. The selection of appropriate preclinical experimental models, most reflective of the complexities of different cancers, may help to identify the most promising therapeutic agents that would sustain the rigour of clinical evaluation. Moreover, it has now become evident that elucidation of “driver” molecular changes can identify patients most likely to benefit from specific targeted therapy. It is therefore expected that the development of new anti-cancer agents should proceed together with the identification of predictive biomarkers of response which should be evaluated early in the discovery phase.

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Last update: 02 August 2012