Drugging the cancer genome: design of personalised cancer medicines


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Paul Workman
Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, Sutton, UK

Abstract

<p>In this lecture I will present our latest results on discovering and developing new drugs that are directed at exploiting those abnormalities in the genomes of cancer cells that are responsible for driving the process of malignancy. I refer to this as “drugging the cancer genome” (Workman, Cold Spring Harb Symp Quant Biol. 70:499-515, 2005; Workman Curr Opin Investig Drugs 8:445-6, 2007).</p><p>We now understand in considerable detail the molecular defects that are involved in the causation and progression of cancer, but we don’t know everything and it will take quite a while to figure out all the details. However, we do know enough to intervene therapeutically in a rational way (Collins and Workman, Nature Chem Biol 12: 689-700, 2006; Workman and De Bono, Curr Opin Pharmacol. 8:359-62, 2008). 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 are achieving selective effects with new targeted therapies based on the exploitation of mechanisms such as oncogene addiction, other cancer dependencies including stress pathways, and synthetic lethality. We are exploiting new technologies to move faster from gene to drug, including high-throughput screening, structure-based design and biomarker discovery. And we are already seeing that patients are gaining considerable therapeutic benefit from our new targeted drugs. On the other hand, there are formidable challenges: in particular, overcoming drug resistance and feedback loops; the design of optimal combinatorial therapies; the targeting of heterogeneous tumour populations and of tumour stem cells; and the development of the best biomarkers to show proof of concept and select responsive patients.</p><p>I will explore progress and future potential in the design and development of small molecule inhibitors of oncogenic pathways, focusing on two areas of the our work that are attracting considerable current interest and for which our first drugs are now undergoing early clinical trials: The HSP90/HSP70 chaperone pathway (e.g. NVP-AUY922; Eccles <i>et al</i>, Cancer Res. 68:2850-60, 2008) and the PI3 kinase pathway (e.g. GDC-0941; Raynaud <i>et al</i>, Mol Cancer Ther. 8(7): July 2009). Coupled with cancer genome sequencing and systems-based cancer network information, the discovery of targeted therapeutics is moving us inexorably towards the goal of personalized molecular cancer medicine.</p><p><i>Declaration of competing interest for Prof Paul Workman: Chroma Therapeutics (Scientific founder, stock holder, Board member, Consultant/SAB member, research funding); Piramed Pharma (now acquired by Roche; Scientific founder, former stock holder, Consultant/SAB member, research funding); Avalon Pharmaceuticals (now acquired by Clinical Data (stock holder and SAB member); Yamanouchi/Astellas (research funding); Vernalis (research funding, HSP90 intellectual licensed to them and Novartis; also former consultant to Novartis); Genentech (PI3 kinase intellectual property licensed to them and Piramed/Roche); AstraZeneca (funded research on chaperone/stress pathways and PKB intellectual property licensed to them and Astex Therapeutics).</i></p><br>