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Development of the human cell GADD45a assay enabled accurate identification of carcinogens in vitro, with a low rate of misleading positives. Through the spin-out company Gentronix, this research is reducing costs to industry and decreasing the use of animals in research. Industrial collaboration has enabled commercial adoption of the technology in many sectors. With a 10-fold increase in orders in 2012 versus 2008, Gentronix is a profitable business employing 17 people and with an annual turnover of £1.88m. During 2008-12, Gentronix released a series of new products, established testing services, and signed a product license agreement with GlaxoSmithKline. More than 100 companies worldwide are using Gentronix kits, including pharmaceutical, agricultural and health and beauty companies, along with manufacturers of food flavourings and household goods. The Gentronix assay is currently being reviewed by the European Centre for the Validation of Alternative Methods.
Newcastle research selected the DNA repair enzyme poly(ADP-ribose) polymerase (PARP) as a promising target for cancer therapy. The first-in-class PARP inhibitor, rucaparib, was developed at Newcastle, in collaboration with Cancer Research UK and Agouron Pharmaceuticals, and subsequently became the first PARP inhibitor to be used to treat a cancer patient in a clinical trial. Currently, at least 8 PARP inhibitors are being developed and major pharmaceutical companies have to date invested around $385 million in clinical trials, and over 7,000 patients worldwide have been treated with PARP inhibitors in trials since 2008, demonstrating the importance of basic and translational research in universities to drug discovery by pharmaceutical companies.
Clinical pharmacology studies conducted at Newcastle have led to optimisation of the administration of the chemotherapy drug carboplatin in children with neuroblastoma and other cancers. The research provided the rationale for carboplatin dosing based on patient renal function, with individualised dosing resulting in increased drug efficacy and reduced toxicity. This approach is now in widespread use in national and European treatment protocols, benefitting over 2,500 children. Similar drug monitoring approaches are being implemented for an increasing number of important drugs. Following a recent Newcastle-led national clinical trial, new dosing guidelines for the drug 13-cis retinoic acid have been adopted for high-risk neuroblastoma patients across Europe.
Bladder cancer is the fifth most common form of cancer, with over 70% of cases presenting as non-muscle invasive bladder carcinomas (NMIBC). Research in the Institute of Cancer Therapeutics at the University of Bradford led to the evaluation of Apaziquone (EO9) in phase II clinical trials against high risk NMIBC in The Netherlands, and two multi-centre phase III clinical trials involving 106 centres across the USA, Canada and Europe. A total of 1,746 patients with low or high risk NMIBC received EO9 and significant reductions in the rates of recurrence at two years have been reported. Our research has impacted upon the health and welfare of patients with NMIBC.
Doses of cytotoxic drugs for chemotherapy need to be determined on an individual basis for each patient and are generally calculated using Body Surface Area (BSA). Traditionally, this meant that doses of cytotoxic drugs needed to be prepared at `the bedside', resulting in safety issues, significant wastage and placed an enormous burden on the time of healthcare workers. `Dose-banding' is a system whereby chemotherapy doses, calculated using BSA or other means, are then fitted to pre-defined dose ranges, or `bands'. This system allows for `standard' syringes or infusions to be batch-prepared by the hospital pharmacy, or even pre-prepared and purchased from an external commercial source.
Research at the University of Bath, conducted between 2000 and 2007, pioneered the establishment of dose-banding as a practice and, through its spin-out commercialisation vehicle, Bath Aseptic Services Unit, Ltd. (Bath ASU), demonstrated that the batch production of cytotoxic drugs according to dose-banding is a viable commercial proposition.
Today, dose-banding is accepted around the world as a valid method of dosing cytotoxic therapies and, since 2008, has had a profound economic and social impact on the healthcare sector through improved patient care, changes to purchasing policy and improved health outcomes. In fact, the impact of dose-banding is so significant in the UK that NHS cancer trusts now recommend that dose-banding should be implemented to manage capacity before investing in staff and facilities.
Bath ASU now supplies over 150 NHS hospitals and pharmacies with upwards of 500,000 doses of injectable `specials' per year (supplying around 30% of the entire UK commercial compounding market), employing over 70 full-time staff and currently generating revenues of over £20M per year.
The safety assessment of drugs and other chemicals relies upon studies in experimental animals. Whilst these are useful surrogates, extrapolation to humans requires several assumptions. Professor Boobis led an international group under the auspices of the World Health Organisation (WHO), to develop a framework for the systematic and transparent assessment of such experimental data. Within this framework, the toxicological effect of a chemical is broken down into a series of intermediate steps, comprising a mode of action. This enables qualitative and quantitative comparison between experimental animals and humans. The framework has impacted on risk assessment policy both nationally and internationally, on product development, and on risk assessments of combined exposure to chemicals.
Drug development is a highly regulated environment. Identifying the need for an independent, academic-led centre of excellence in research and training of pharmacokinetics, we established the Centre for Applied Pharmacokinetic Research (CAPKR) to engage in problems of generic interest to the Pharmaceutical Industry. CAPKR has been highly influential by informing regulatory practice in Europe and the USA, by establishing and optimising industrial practices related to drug development, particularly those related to drug-drug interactions, by reducing the usage of animals in research and by allowing the commercial development and extensive use of simulation software tools for quantitative prediction of pharmacokinetics in order to improve patients' safety.
A new method for classifying aircraft accidents and modelling the effectiveness of runway end safety areas was developed by Pitfield and colleagues at Loughborough University (1997-present) to improve global airfield safety. It was adopted by the US Airports Cooperative Research Program in 2008, validated at eight airports, and empirically applied at three, including San Francisco and Toronto (2009-2010). It resulted in: the use of enhanced aircraft accident modelling methodologies by aviation practitioners; improvements to global airport risk assessment and safety management regimes; the utilisation of empirical techniques by a commercial consultancy; and evidence being presented to the 2011 UK Public Inquiry into the proposed expansion of London Ashford Airport.
Researchers at Newcastle University discovered interactions in vitro between the widely prescribed cholesterol-lowering drug rosuvastatin and cyclosporine, and between rosuvastatin and gemfibrozil, at the liver transporter protein OATP1B1. Subsequent clinical trials showed that the interactions occurred in patients and slowed clearance of rosuvastatin from the body. The research findings not only had direct implications for the safe prescribing of rosuvastatin when it came to be marketed but also more far-reaching impact. US Food and Drug Administration and European Medicines Agency guidelines published in 2012 stipulate that pharmaceutical companies must investigate potential drug-drug interactions in the pre-clinical development phase of all candidates that bind that transporter.
Research by Professor Steve Jackson led to the discovery of synthetic lethality as a means of selectively targeting cancer cells, and to Jackson founding KuDOS Pharmaceuticals to translate this research into therapies. This novel approach has changed the way pharmaceutical companies develop cancer therapeutics and has led to several drugs reaching pre-clinical and clinical development. The most advanced of these (olaparib, a PARP inhibitor originally developed at KuDOS and acquired by Astra Zeneca) is now entering Phase 3 trials and registration in Europe. In 2011, Jackson founded MISSION Therapeutics Ltd, to extend the synthetic lethality concept into targeting deubiquitylating enzymes to selectively kill tumour cells.