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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.
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.
Work by Professor Andrew Tutt at King's College London (KCL), has had the following major impacts: (i) it has provided proof through first-in-man clinical trials (in collaboration with the Royal Marsden/ICR Phase I Clinical Trials Unit) and Phase II clinical trials designed and led by Professor Tutt that poly(ADP ribose) polymerase (PARP) inhibitors have an anti-cancer action in breast and ovarian cancers with BRCA mutations; (ii) it has demonstrated that the concept of `synthetic lethality' can be applied to the selective targeting of cancer cells in humans; (iii) it has paved the way for a major programme of investment by the pharmaceutical industry (over $1 billion to date) in PARP inhibitors for the treatment of BRCA-related cancers (which are currently being tested in a range of cancers in Phase III trials); and (iv) it has been incorporated into UK, European, US and other international guidelines on genetic testing for breast and ovarian cancers that run in families.
Newcastle University research discovered the first potent inhibitors of the DNA repair enzyme poly (ADP-ribose) polymerase 1 (PARP-1) through medicinal chemistry and preclinical work leading to first-in-man clinical studies. This research led to the development of Rucaparib, an agent that inhibits the ability of cancer cells to survive drug treatments or radiotherapy. As a result of Newcastle's research a further 8 PARP inhibitors are in development. Major pharmaceutical companies have invested an estimated $385 million in clinical trials, with at least 7000 patients enrolled in PARP inhibitor trials since 2008. Cancer patients worldwide have already been successfully treated with these new anti-cancer drugs.
Scientists at The Institute of Cancer Research (ICR) have identified a breast cancer susceptibility gene, BRCA2, and advanced the understanding of the function of the BRCA genes. Following the discovery and cloning of BRCA2, further research demonstrated that BRCA mutations are also associated with ovarian, prostate and pancreatic cancers. BRCA testing is now routinely used by health services worldwide to identify those at high risk of developing cancer and advise them on preventative strategies. ICR research showed that magnetic resonance imaging (MRI) was more sensitive than X-ray mammography when screening for tumours in BRCA carriers, and this is now the standard of care in the UK. Through further research on BRCA function, ICR scientists demonstrated that PARP inhibitors were effective in treating breast cancer in mutant BRCA carriers. This has led to the rapid development of poly-ADP-ribose polymerase (PARP) inhibitors as drugs for targeted use against breast and ovarian cancers with a BRCA mutation as well as a recent submission to regulatory authorities for approval and registration in Europe for the use of the PARP inhibitor olaparib for maintenance treatment of BRCA mutated ovarian cancer.
A first-in-class anticancer agent discovered in Thurston's laboratory at the University of Portsmouth in the 1990s has been commercially developed and clinically evaluated over the last two decades. SJG-136 was successful in Phase I clinical trials and is completing Phase II clinical trials for the treatment of ovarian cancer and leukaemia, where significant patient benefit is observed. Related molecules based on this parent compound are in drug programmes being undertaken by Seattle Genetics Inc. and Genentech Inc., leading to additional clinical trials. A spin-out company, Spirogen Ltd, was established in 2000 to commercialise the intellectual property generated from the underpinning research, and the company has recently been sold to AstraZeneca for $200m.
A novel test for prostate cancer was developed from research in mitochondrial genetics conducted at Newcastle University. The Prostate Core Mitomic Test was the first of its kind and is now commercially available in North America. It provides molecular evidence to confirm conventional pathology results showing that men identified as being at risk of prostate cancer are, at the time of examination, free of disease. This is an important patient benefit, as conventional pathology has a 30% chance of missing prostate cancer. The Mitomic test obviates the short-term need for a follow-up biopsy, which is an invasive and very uncomfortable procedure. It is also capable of identifying some men at high risk of having prostate cancer that conventional pathology would miss. The test was introduced to the American market in June 2011 and has generated a multi-million dollar investment and turnover.
The Caldecott/Jeggo/O'Driscoll laboratories have identified human genetic diseases that are caused by defects in genes involved in DNA strand-break repair. Many of these diseases are associated with neurological pathologies such as cerebellar ataxia (resulting in poor balance, movement control, and patients often being wheelchair bound), microcephaly (smaller-than-normal head circumference), and developmental delay. The Caldecott/Jeggo/O'Driscoll laboratories have engaged in identifying/diagnosing patients with such diseases as a service to clinicians/clinical geneticists in the UK National Health Service (NHS) and worldwide. Since 2008, these laboratories have identified the underlying genetic defect in more than 150 patients with a range of hereditary DNA damage-related disorders. In particular, these laboratories have diagnosed patients with genetic defects in the DNA damage response genes Lig4, NHEJ1-XLF, DCLRE1C-Artemis, PRKDC-DNA-PKcs, PCNT, ORC1, ATRIP, ATR, and TDP2. These diagnoses benefit both the clinical geneticist and the patient; identifying not only the cause of the patient's disease but also enabling better disease management. For example, if not first diagnosed, standard chemotherapeutic regimes can be fatal in cancer patients who harbour homozygous TDP2 mutations, and standard conditioning regimes used during bone-marrow transplantation can be fatal in LIG4 Syndrome patients. These diagnoses can therefore translate into increased patient survival.
Through their study of DNA polymerases from organisms of the domain archaea, researchers at Newcastle University and University College London identified the mechanism by which these organisms avoid potentially damaging mutations in their DNA. As a consequence of this work they invented a novel genetically-engineered DNA polymerase. This enzyme has been patented and is the world's only high-fidelity, proofreading DNA polymerase that efficiently reads through uracil in the polymerase chain reaction (PCR). PCR is a very widely used technique in biomedical research. An international bioscience company [Text removed for publication, EV d] signed a licensing agreement with Newcastle University in 2008 to market the enzyme, and total sales since 2008 exceed [Text removed for publication, EV d]. Further commercial exploitation has begun through licensing agreements with other major companies.
Cancer research at the University of Salford focuses on developing new and improved treatments for cancer, particularly for children with cancer, demonstrating the following impact: