The View From Here
Drugging the cancer genome
This is an extraordinarily exciting time for cancer research and the development of new cancer drugs. Over the last few years we have moved firmly out the cytotoxic era and into the new era of molecularly targeted drugs. The transition has in many ways been paralleled by the history of drug discovery at my own institution, The Institute of Cancer Research (ICR; http://www.icr.ac.uk/), which celebrates its centenary this year. In this editorial I will illustrate the evolution of the field using examples from ICR work in the context of the broader arena.
Recent progess in cancer drug discovery, especially over the last decade, has been driven by our increasingly sophisticated, though still incomplete, understanding of the genetic abnormalities that drive oncogenesis, operating through the hijacking of mission-critical signal transduction pathways in the cell. In the last few years the sequencing of cancer genomes has revealed the genetic landscape of malignant diseases, identifying mutated genes and deregulated pathways that are key targets for therapy – and thereby opening up prospects for true personalized cancer medicine.
The first clinical successes in cancer chemotherapy in the late1940s involved the use of the DNA cross-linking agent nitrogen mustard – based on the sulphur mustard war gas – and the antifolate aminopterin. At ICR, early investment in drug discovery led to the design, synthesis and clinical development of the DNA alkylating agents melphalan, chlorambucil and busulphan, drugs that are still in use today worldwide, particularly in haematological malignancies.
Much more recently, our work in this area has focused on the targeted activation of nitrogen mustard prodrugs at the tumour site by using antibody-directed enzyme prodrug therapy (ADEPT, in collaboration with Cancer Research UK)) and gene-directed enzyme prodrug therapy (GDEPT), including the design and synthesis of the mustard prodrug ZD2767P.
The discovery and development of platinum drugs at ICR resulted in carboplatin (with Johnson Matthey and Bristol-Myers Squibb) which is now widely used in lung, head and neck cancers). Later platinum drugs from ICR included satraplatin (a third generation oral platinum drug for hormone refractory prostate cancer and ovarian and lung cancer) and picoplatin (another third generation platinum undergoing trials in small cell lung cancer, metastatic colorectal and hormone-refractory prostate cancer).
Antifolate work at ICR led to the discovery and development (with AstraZeneca) of the thymidylate synthase inhibitor Tomudex (raltitrexed) that is approved for the treatment of advanced colorectal cancer. Further work produced BGC9331 (previously ZD9331) that overcomes a major mechanism of resistance. More recently, our novel thymidylate synthase inhibitor that is targeted to cancers overexpressing the alpha-folate receptor was licensed to Onyx Pharmaceuticals and is undergoing preclinical development as ONX 0801 (previously BGC 945).
The cytotoxic and molecularly targeted eras were in a sense bridged by the development of antihormonal drugs for breast and prostate cancer, which exploit dependencies inherited from the original precursor cells. At ICR, we carried out the design, synthesis and development of abiraterone acetate. This drug was licensed to Cougar Biotechnology, recently acquired by Johnson & Johnson. It is an orally administered CYP17 inhibitor that blocks testosterone (and oestrogen) production. Abiraterone has shown very promising activity in castrate-resistant prostate cancer and is currently in Phase III trials.
The last few years have seen the progression of an exciting pipeline of late stage drug discovery projects at ICR, with targets including Hsp90 (with Vernalis and Novartis), PI3 kinase (with Piramed and Genentech), AKT/PKB (with Astex and AstraZeneca), CDK (with Cyclacel), Aurora, BRAF (with Wellcome Trust), CHK1(with Sareum) and CHK2. Centred on the Cancer Research UK Centre for Cancer Therapeutics and our collaborators at ICR and elsewhere, most of these projects are partnered with biotech and pharma companies.
Inhibitors of the Hsp90 molecular chaperone block multiple oncogenic signaling pathways to which cancer cells are “addicted.” The iv drug NVP-AUY922, discovered by ICR in collaboration with Vernalis and licensed to Novartis, is now in Phase I clinical trial. A second oral candidate NVP-BEP800 emerging from this research programme was recently disclosed. This work exemplifies a number of modern approaches used in structure-based drug design.
Our work leading to the discovery of PI3 kinase inhibitors has involved many partners. Early work with Yamanouchi (now Astellas) led to the founding of Piramed Pharma (subsequently acquired by Roche) by ICR, Cancer Research UK and the Ludwig Institute. The subsequent research programme between ICR and Piramed resulted in Genentech’s GDC-0941, now in Phase I clinical trial.
Another ICR/Cancer Research UK spinout company, Chroma Therapeutics, is developing inhibitors of aminopeptidases and chromatin modifying enzymes, with agents now in the clinic.
Recent clinical studies showing the exciting early activity of the AstraZeneca PARP inhibitor olaparib in patients with BRCA1/2 mutations were based on preclinical studies at ICR/Breakthrough. This is the first example of the clinical exploitation of “synthetic lethality.”
Over the last 5 years a total of 13 preclinical development candidates have been nominated from our work at ICR.
In addition to the late stage development projects, ICR has an exciting early stage portfolio, including new second generation molecular chaperone and stress protein targets that we and others have validated, one area of which is partnered with AstraZeneca. Also of note are inhibitors of the oncogenic phosphatase PPM1D that ICR/Breakthrough/Cancer Research UK recently partnered with Antisoma and WNT pathway inhibitors involving a partnership between ICR, Cancer Research UK, Cardiff University and MerckSerono.
There are a number of messages emerging from this experience at ICR that have a wider resonance. One is obviously the evolution from cytotoxic to molecularly targeted drugs that exploit tumour dependencies and hence should be more effective and less toxic. Also important is that, at a time when there are extraordinary molecular opportunities and at the same time great pressures on the pharmaceutical and biotechnology industry, there is an increasing opportunity for non-profit drug discovery and development groups to de-risk projects that carry high levels of biological or technical risk, for example by demonstrating proof of concept. Another message is the value of working in partnership with various organizations to help accelerate the pathway from gene to drug for patient benefit.
There is a revolution underway. Modern cancer drug development is targeted to populations of patients that will be characterized by their genetic and molecular status rather the anatomical site or histological appearance of their tumours. Looking to the future, there are exciting prospects for truly personalized molecular cancer medicine. This requires biomarkers that are scientifically and technically well validated and clinically credentialed for use alongside our molecularly targeted drugs. This is an exciting current challenge. Examples already exist in the case of mutant KIT for therapy with imatinib in gastrointestinal stromal tumours, overexpressed ERRB2/HER2 for treatment of breast cancers with trastuzumab, mutant epidermal growth factor receptor (EGFR) for therapy with EGFR inhibitors gefitinib and erlotinib in non small cell lung cancers, and wild type RAS for treatment with EGFR-targeted antibodies like cetuximab in colorectal cancers. Looking even further ahead it will be important to use multiple biomarkers and to define cancers in terms of dynamic systems or networks – involving key nodal points and the inevitable feedback loops – and eventually to treat malignancies using an individualized systems medicine approach. The tools are now being assembled for this and it may happen sooner than we think.
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Workman P, de Bono J. Targeted therapeutics for cancer treatment: Major progress towards personalised molecular medicine. Curr Opin Pharmacol 2008; 8:359-62.
Paul Workman is Director of the Cancer Research UK Centre for Cancer Therapeutics, Section Chair of Cancer Therapeutics and Harrap Professor of Pharmacology and Therapeutics at The Institute of Cancer Research (ICR), Sutton, UK. He heads the biggest academic cancer drug discovery group in the world.
Paul has spent >30 years in cancer drug discovery and development, including periods in academia, biotech and large pharma. He was previously Cancer Research Bioscience Section Head at AstraZeneca where he led the biology team on the discovery of gefitinb (Iressa) which is now approved in non small cell lung cancer. While at AZ he also initiated and led the research collaboration with Sugen.
Paul was a scientific founder of Piramed Pharma, which was acquired by Roche for USD 175M in 2008, and of Chroma Therapeutics, which recently announced a £15M Series D financing and a research collaboration with GSK.
Paul has been responsible for or closely associated a number of cancer drugs that have entered clinical trial. He has authored over 400 peer reviewed research articles and reviews on cancer drug discovery and development. His particular current interests are in drugging molecular chaperones and the PI3 kinase pathway. Paul is a Cancer Research UK Life Fellow and a Fellow of the Academy of Medical Sciences.He enjoys music and Manchester United