Pharmacogenomics in cancer drug discovery and development

P Workman

CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, Surrey, SM2 5NG UK,

Drug discovery is being revolutionised by a number of technological developments. These include high throughput screening, combinatorial chemistry and genomics. The impact of the new technologies is to accelerate the pace of anticancer drug discovery. The completion of the Human Genome Project and the ongoing high throughput sequencing of cancer genomes will facilitate the identification of a range of new molecular targets for drug discovery (Workman Curr Opin Pharmacol 1 342-352 2001). Over the next few years, we will have a complete molecular understanding of the various combinations of genes and cognate pathways that drive the malignant phenotype and tumour progression. The vision for postgenomic cancer drug discovery must now be to identify therapeutic agents that correct or exploit each of these molecular abnormalities. In this way, it will be possible to develop personalised drug combinations that are targeted to the molecular make up of individualised tumours. It is anticipated that these therapies will be more effective and less toxic than current approaches, although combinations of novel agents with existing cytotoxic therapies are likely to continue for some time. Examples of postgenomic, mechanism-based drugs include Glivec, Herceptin and Iressa, with many more agents undergoing preclinical and clinical development. An interesting new approach involves the development of inhibitors of the Hsp90 molecular chaperone (Maloney and Workman, Expert Opin Biol Ther (2002) 2 3-24). Because Hsp90 is required for the correct folding, stability and function of a range of oncoproteins that are mutated or overexpressed in cancer, Hsp90 inhibitors have the potential to provide a simultaneous combinatorial attack on multiple oncogenic pathways. Progress in the preclinical and clinical development of Hsp90 inhibitors will be described, including an update on clinical studies with the first-in-class agent 17AAG. The use of the postgenomic technology of gene expression microarrays in cancer pharmacology and drug development will be exemplified (Clarke et al, Biochem Pharmacol 62 1311-1136 2001). Supported by the Cancer Research Campaign (CRC). Professor Paul Workman is a CRC Life Fellow. For more information on the CRC Centre see

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Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Molecular Genetics & Therapy - 2.