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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.
Cancer is a widespread deadly disease; annually, one million new breast cancers are diagnosed globally. Endometriosis is a poorly understood disorder, with 80 million patients worldwide. Current therapies for both are inadequate and discovery of new drugs is critical. The Bath group has pioneered identification of new targets and designed two "first-in-class" clinical drugs. The Bath/Imperial College spin-out company Sterix (subsequently acquired by a major pharmaceutical company) has translated them into patients and to the pharmaceutical industry. The steroid sulfatase inhibitors, Irosustat and J995 have entered eighteen clinical trials worldwide in patients with these hormone-dependent diseases, with several ongoing since 2008. Disease was stabilised for cancer patients; the advanced clinical evaluation of both drugs is in progress.
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.
Researchers at the University of Sheffield developed a novel tailored therapy for some forms of breast cancer. This was the first example of the selective killing of a tumour using an inhibitor of a DNA repair enzyme (PARP) to induce synthetic lethality, heralding an era of personalised cancer therapy. The discovery was patent protected and development rights sold to Astra-Zeneca who undertook successful phase I and II clinical trials. Disclosure of the findings stimulated intense investment in research and development and has revolutionised approaches to cancer therapy. There are now eight PARP inhibitors in phase I to III clinical trials (92 currently listed involving several leading pharmaceutical companies and thousands of patients) targeting a wide range of tumour types.
The Cancer Research UK Formulation Unit at the University of Strathclyde performed the pharmaceutical research and development of new chemotherapy treatments for malignant brain and prostate cancer (temozolomide and abiraterone acetate). These two drugs are now marketed globally, with FDA approval for the US market in 1999 and 2011 respectively, and have directly improved the quality of life and increased survival rates during treatment for over a quarter of a million cancer patients annually since 2008. Temozolomide achieved $1 billion sales per annum in 2008, and Abiraterone global sales reached $1.45 billion by 2013. Both drugs have produced economic benefit to the charity Cancer Research UK through royalty payments.
Research at the UCL Cancer Institute into drug-DNA interactions has led to spin-out company Spirogen Ltd resulting in job creation (currently 25 employees) and significant investment from within the UK and overseas. Pyrrolobenzodiazepine dimer drug (SJG-136, SG2000) is currently in clinical trials in the USA and collaborative research and licence agreements in the area of antibody drug conjugates have been established with large pharmaceutical partners including in 2011 with Genentech, a member of the Roche group. In 2013, Spirogen was acquired by Astra-Zeneca for $200m.
The PI3 kinase (PI3K) enzymes play a significant role in AKT-mTOR intracellular signalling, a key pathogenic pathway in many cancers. The ICR has discovered first-in-class inhibitors of class I PI3K and these are now being commercially developed by Genentech and are in clinical trials, having demonstrated clinical safety, as well as target inhibition and antitumour activity. To accelerate the commercial development of its PI3K inhibitors, the ICR founded the spin-out company Piramed Pharma, which was subsequently acquired by Roche for a total of $175million. The ICR's published research and its development of a tool compound has underpinned the worldwide effort by pharmaceutical companies to develop these novel cancer therapeutics.
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:
Bowel cancer is the third most frequently diagnosed cancer worldwide. University of Glasgow researchers have established Xeloda (an oral 5-fluorouracil precursor) and XELOX (a chemotherapeutic regimen combining Xeloda with oxaliplatin) as highly effective, targeted therapies for patients with bowel cancer. Since 2008, European regulatory approval of these therapies has been incorporated into major international clinical guidelines. The research has transformed patient care by improving the treatment experience, with more convenient dosing schedules and fewer side effects compared with previous chemotherapy procedures. Xeloda and XELOX have transformed chemotherapy for bowel cancer and decreased therapeutic costs, potentially saving around £4,762 (Xeloda) and £947 (XELOX) per patient for the NHS.
Thousands of people across the world with a genetic predisposition (HNPCC) to bowel cancer, together with the population at large, have benefited from research on aspirin and dietary fibre undertaken at the University of Bristol since 1993. Clinical trials involving the Bristol group show that the incidence of bowel cancer has fallen in HNPCC patients who take aspirin. Moreover, aspirin use after diagnosis of bowel cancer has reduced colorectal cancer mortality. Furthermore, a high fibre diet also lowers the risk of bowel cancer. These studies led to national public health initiatives (such as the `five-a-day' campaign) that have been instrumental in increasing public awareness of the importance of aspirin and dietary fibre in reducing the risk of bowel cancer, and in establishing international guidelines on dietary advice.