Introduction: novel therapies from gene to drug
Paul Workman
The Institute of Cancer Research, Sutton, UK
We now understand in considerable detail the molecular defects involved in the causation and progression of cancer. We don’t know everything and it will take quite some time to work out much of the detail. But we do know enough to intervene therapeutically in a rational way (Collins and Workman Nature Chem Biol 12 689-700 2006). We understand the basic principles of oncogenesis, involving mutations in, and epigenetic changes to, key genes that regulate mission-critical pathways. We have sufficient knowledge to engage in mechanism-based drug development targeted to the genes and pathways that are hijacked in human cancers. We can expect to achieve selective effects of new targeted therapies based on the exploitation of mechanisms such as oncogene addiction, other cancer dependencies and synthetic lethality. We can exploit new technologies to move faster from gene to drug. And we have seen worked examples, such as imatinib and trastuzumab, that teach us that patients can derive considerable therapeutic benefit from the new targeted drugs. On the other hand, there are formidable challenges: in particular, overcoming drug resistance, the design of optimal combination therapies, the targeting of heterogeneous tumour populations and of tumour stem cells, and the development of biomarkers to show proof of concept and select responsive patients.
So is the glass half empty or half full? In this session we will explore progress and future potential using as examples inhibitors of three oncogenic pathways that are attracting considerable current interest and for which the first drugs are now entering the clinic: the HSP90 chaperone pathway, the PI3 kinase pathway and the HIF pathway, all of which are deregulated in human cancers.
