Cancer drug development in the post-genomic age

The last two decades have brought remarkable progress in our understanding of the molecular basis of cancer. It is likely that the classification of t umours by their molecular phenotype will provide the key to predicting thei r natural history and response to treatment. Such systems will replace conv entional histological approaches within the next five years. Functional gen omics, proteomics, the development of novel animal models for human cancer and the ability to accurately verify biochemical targets have yielded sever al exciting platforms on which to develop novel therapies. The dramatic inc rease in the pace of discovery of new molecules for clinical trial will req uire innovative approaches for their clinical development. To enhance the speed of assessment, it will be essential to identify surrog ate endpoints to validate the effectiveness of a potential drug. In the sho rt term such assays will determine the activity on a specific molecular tar get in vivo and allow the construction of dose response curves, often in he althy volunteers. This is a radical departure from cytotoxic drug developme nt. The use of such pharmacodynamic endpoints will replace the current phas e I dose escalation schedules by which the maximum tolerated dose of a canc er drug is determined. Once the maximally effective dose has been identified, surrogate endpoints of effectiveness to halt tumour progression will be required. Such markers may include the release of specific tumour DNA fragments into serum, the qu antitation of novel tumour markers or the identification of downstream effe cts of tumour growth delay such as apoptosis, necrosis or the interaction w ith local blood vessels. Biochemical markers are being sought but other app roaches such as positron emission tomography, nuclear magnetic spectroscopy , isotope scanning and a range of innovative non-invasive imaging systems w ill provide useful data on protein phosphorylation and even specific mRNA e xpression. It is conceivable that genetic indicator systems, introduced by direct injection into tumours, will yield information on both the effect of the drug locally and the response of cancer cells to it. Sophisticated arr ay systems will soon be available to monitor patterns of gene expression be fore and after therapy. Such techniques will enhance the speed of early can didate drug selection and reduce the risk of later failure. They will almos t certainly form part of future regulatory packages. The diverse nature of these highly specialized techniques will by necessity concentrate the early phase of drug development in a few centres of excellence rather than the c urrent diffuse pattern. Leveraging the clinical-scientific interface in cancer research is the key component in accelerating the development of novel therapies. Creating inno vative partnerships between an increasingly consolidated and globalized ind ustry and major cancer treatment centres is now essential to enhance the sp eed of drug development. Currently 370 compounds are undergoing clinical tr ial for cancer, and this number can confidently be expected to reach over 5 00 by the end of 2001. There has been a significant shift to the exploratio n of molecules with novel mechanisms of action during the last three years.