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University of Sheffield - Articles and news items
Protein kinases represent a vast, partially untapped resource of drug targets for therapeutic intervention in human disease. The remarkable success of the tyrosine kinase inhibitor Imatinib, which is now the first-line therapy in Philadelphia-positive tyrosine kinase inhibitor Imatinibhas galvanised biomedical researchers in an attempt to repeat the landmark success of this ‘bench-to-bedside’ approach to therapy. Imatinib inhibits the BCR-ABL fusion kinases responsible for driving these cancers, and its clinical efficacy provides compelling molecular evidence that this drug elicits life-extending clinical responses through an ‘on-target’ mechanism. Interestingly, Imatinib has several additional (non-ABL) protein kinase targets including oncogenic KIT, which also allows it to be employed for the treatment of high-risk Gastro Intestinal Stromal Tumours…
As RNA interference (RNAi) enters its teenage years from the first critical observations, it has now reached a multi-billion pound industry. There are few research areas that have expanded as quickly and spectacularly as the field of RNAi. The potential of RNAi initially sparked a functional genomics gold rush. Different uses of this technology in genomewide screens have identified genes involved in fundamental biological processes. There are now hundreds of research papers reporting genome-wide screens using cell culture to investigate the building blocks of the cell. However tempting it may be to speculate that this technology could be the new magic bullet to all our research needs, especially after some of the previous successes, some basic aspects of the RNAi technology and screening process still need to be addressed and improved upon. This review will investigate the strengths and weaknesses of our current technology, suggesting improvements and highlighting some of the novel growth areas in this field.
Our foundations of cell biology rely upon an understanding of cellular pathways, the components of which have been investigated over the last 40 years or so. Recent embellish – ment of the pathways has been carried out using models in cell culture with RNAi technology1. Many techniques have been used to reveal the functions of core pathway proteins, but few have sparked the imagination like the RNAi screen with the potential to systematically knock down the expression of every gene in the genome.
The Canadian physician William Osler said: “The person who takes medicine must recover twice, once from the disease and once from the medicine.” Indeed, all medicines have side effects – some of which may complicate a patient’s treatment, or in extreme cases may even be fatal. Of concern is the fact that side effects of drugs are often difficult or impossible to predict from preclinical studies, and infamous cases of drugs causing permanent injury or even death of patients in clinical trials illustrate the severity of this problem.
Late stage attrition of drugs is costly for pharmaceutical companies, contributing to the rise of drug prices and delays of drug delivery to market. Better prediction of compound efficacy and safety at early stages of drug development relies on improvement of the models used for pre-clinical testing. The availability of human embryonic stem (hES) cells and, more recently, induced pluripotent stem (iPS) cells may transform the landscape of drug discovery. Here we provide an overview of human pluripotent stem cell features that make them amenable to predictive toxicology and discuss how chemical screens that aim to find drugs that modulate stem cell fates may provide a paradigm for using stem cells in drug discovery.
1. What do you feel are the current changing attitudes to Stem Cell Research?
Paul Andrews: First of all are we talking throughout this roundtable about human stem cells? Are we differentiating between human embryonic stem cells and adult stem cells, or patient-derived induced pluripotent stem (iPS) cells? The differences in attitude and responses could be completely different. In addition: what do we mean by research: research aimed at therapy; for drug testing that might reduce reliance on animal models and lead to better drug safety; or basic cell biology research?
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