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Biography |
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David Kerr has been given a 5 year leave of absence from the University of Oxford to become the Chief Scientist for SIDRA, an academic Health Science Centre (www.sidra.org) endowed with $ 8 billion, and Director of Qatar’s national Biomedical Research Institute. From there, he plans to build a collaborative biomedical research network through the Middle East and contribute to improving Global Health. He has been appointed to the Supreme Council of Health, effectively Qatar’s Health cabinet, practices medicine in ‘Al Amal Cancer Hospital’ and contributes to Oxford as Professor of Cancer Medicine where he has worked with colleagues to build a new Institute for Cancer Medicine and Cancer Hospital. He is internationally renowned for his contributions in the treatment of and research into colorectal cancer. He is currently developing new approaches to cancer treatment which involve novel biomarkers and inhibitors of key biochemical pathways. He was awarded several international prizes and the first NHS Nye-Bevan award for innovation. He has published more than 350 articles in peer-reviewed journals (including New England Journal of Medicine, Lancet, Nature Genetics) and has contributed many books on cancer.
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Abstract |
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Increasingly, Clinical Trials of novel anti-cancer agents combine Innovations in Cancer Drug Development
clinical observation with pharmacokinetic (PK) and pharmacodynamic endpoints (PD) in an attempt to provide proof of mechanism. This should allow refinement of drug development pathways, with the potential to explore success or failure in a rational way, and thus improve the efficiency of drug development.
The oxido reductase NQO2 converts CB1954, in the presence of the co-factor EP0152R, to a cytotoxic bifunctional alkylating agent. NQO2 activity in hepatocellular tumour tissue is 6-fold higher than other cancer types and 20-fold higher than bone marrow. The x-ray crystal structural binding model of CB1954 and EP0152R to NQO2 suggested the optimal infusional schedule for a phase I trial combining the two agents. Thirty-two patients were treated and diarrhoea and transaminitis defined the clinically tolerated dose of the combination. There was remarkable pharmacokinetic interaction, with EP0152R inducing a 1000 fold increase in clearance of CB1954, in keeping with model predictions. The comet assay detected DNA interstrand crosslinks caused by nitroreduced CB1954 in tumour biopsies taken from treated patients, demonstrating proof of mechanism. This trial, therefore gives an example of how the drug development pathway can be mechanistically tested in the clinic.
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