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Sussex scientist unlocks hidden potential of cutting-edge cancer drugs

Professor Laurence Pearl

A class of cutting-edge cancer drugs could keep patients alive for longer than they do now, following a major new discovery by University of Sussex researchers working with the Institute of Cancer Research.

The researchers, who looked at exactly how the drugs attack tumours, have hailed the finding “unexpected and exciting."

The drugs, known as kinase inhibitors, are among the most heralded of the new kind of targeted therapies, with 25 already in use and around 400 under development.  Around 5,000 to 10,000 patients receive the drugs in the UK each year, with that number set to grow as more of the drugs are approved for use.

Kinase inhibitors work across types of breast, skin, lung and kidney cancer, but often only extend life by around three to six months.

The University of Sussex and the Institute of Cancer Research team believe they can unlock the true potential of the drugs by changing the way they are used – after uncovering a hidden mechanism of action.

The study was funded by Cancer Research UK and the Wellcome Trust, and is published today (Sunday 17 March) in the prestigious journal Nature Chemical Biology.

Excitingly, the mechanism identified applied in precisely the same way to each of four kinase inhibitors tested, all of which are already in use as cancer treatments:

  • Vemurafenib, which treats cancers caused by a mutation of a gene called BRAF, including many melanoma skin cancer patients;
  • Lapatinib, which treats patients with aggressive, HER2-positive breast cancer;
  • Sorafenib, which treats many patients with kidney cancer;
  • Erlotinib, which treats many patients with non-small cell lung cancer.

 Researchers found that the conventional assumption of how kinase inhibitors work against cancers told only part of the story.

The drugs had been thought to work solely by blocking the cell signalling function of enzymes called kinases – which play an active role in many cancers – by preventing them from binding to ATP, the basic unit of energy in cells.

The new research found that at high doses, the drugs also prevented kinases from linking up with a complex of molecules in cells called the Hsp90-Cdc37 chaperone system, which is essential for maintaining the stability of proteins. The team showed that this ‘chaperone deprivation’ actually caused the destruction of the cancer-causing kinases and halted the growth and division of cancer cells.

The researchers now plan to conduct clinical trials using kinase inhibitors at higher doses, but with rest periods to take advantage of the new mechanism – and believe the new method has the potential to keep cancers at bay for much longer.

Study co-author Professor Laurence Pearl, Professor of Structural Biology in the Medical Research Council Genome Damage and Stability Centre at the University of Sussex, where he also heads the School of Life Sciences, says: “This discovery could really improve the impact of these targeted treatments, which are already becoming important agents in modern cancer therapy. Our work has revealed their hidden power to promote the destruction of the kinases that drive cancer, which hasn’t so far been exploited in their clinical use.

“It shows how important it is to understand the basic biology of how cancer drugs work. We have more work to do to understand this mechanism fully, but we are optimistic that our discovery will help many patients live for longer.”

Study co-author Professor Paul Workman, Deputy Chief Executive of The Institute of Cancer Research, says: “We already knew these drugs were very effective, but we now think they could be even better. We found that several clinically used kinase inhibitors could not only disable cancer-causing kinases but also cause their destruction. It’s an unexpected and exciting discovery, with major implications for how to dose these drugs to help patients live for longer.

“We hope to launch a clinical trial in the next year to test the benefits of delivering kinase inhibitors in a way that should maximise their impact in destroying their targets. There is more work to do to prove the benefit to patients, but these drugs are already approved so there are fewer regulatory burdens than usual to overcome to test our new idea.”

Dr Julie Sharp, senior science information manager at Cancer Research UK, said: “Cancer Research UK scientists have helped to develop and test a number of kinase inhibitors. Having a better understanding of how these drugs work means that researchers can now try and fine tune their use to make them even more effective and improve survival for cancer patients.”

Dr Michael Dunn, Head of Molecular and Physiological Sciences at the Wellcome Trust, said: “This discovery emphasises the fundamental importance of using biology to help us understand how cancer drugs work.  This is a very surprising and interesting result which could lead to much better therapies in the future.” 

Notes for Editors

Professor Laurence Pearl FRS

Professor Laurence Pearl is Professor of Structural Biology in the Medical Research Council Genome Damage and Stability Centre and heads the School of Life Sciences at the University of Sussex. For the previous 10 years Professor Pearl was Professor of Protein Crystallography at The Institute of Cancer Research, London.

Professor Pearl's seminal contributions to scientists' understanding of the recognition and repair of DNA damage and the function of molecular chaperones such as HSP90, was recognised in 2008 with his election as a Fellow of the Royal Society (FRS).

About the MRC Genome Damage and Stability Centre, University of Sussex

The MRC Genome Damage and Stability Centre is an internationally recognised centre of excellence at the University of Sussex that investigates the responses of cells to genome damage and their relationship to cancer and other aspects of human disease.  Housed in purpose-built laboratories funded by the Joint Infrastructure Fund (JIF), the Wolfson Foundation and the University of Sussex and located adjacent to the University’s School of Life Sciences, the Centre enables scientists of different disciplines to be housed in one building and benefit from mutual interests as they carry out state-of -the-art research.

This research is supported by the Medical Research Council via a Centre Grant, and multiple Programme Grants from the MRC, Wellcome Trust, Cancer Research UK and European Research Council, amongst others. The Centre currently houses 20 research groups, whose work ranges from studies on the protein molecules that repair DNA inside cells, to the genes that are altered or mutated in cancer cells, through to investigations on cancer-prone people to identify other useful targets in the war against cancer.

The University of Sussex was the first of the new wave of UK universities founded in the 1960s, receiving its Royal Charter in August 1961. Sussex is a leading research university with over 90 per cent of Sussex research activity is rated as world leading, internationally excellent or internationally recognised (RAE 2008). The University has counted three Nobel Prize winners, 16 Fellows of the Royal Society, six Fellows of the British Academy and a winner of the prestigious Crafoord and Kyoto Prizes on its faculty.

University of Sussex Press office contacts: Maggie Clune and Jacqui Bealing. Tel: 01273 678 888.

Email: press@sussex.ac.uk

View press releases online at: http://www.sussex.ac.uk/newsandevents/

Professor Paul Workman FMedSci

Professor Paul Workman is one of the world’s leading cancer drug discoverers. He is deputy chief executive of The Institute of Cancer Research (ICR).  He is also director of the Cancer Research UK Cancer Therapeutics Unit at the ICR – the world’s largest multidisciplinary cancer drug discovery and development initiative.

Under Professor Workman’s directorship, the Cancer Therapeutics Unit has helped discover and develop many important new cancer treatments, including the prostate cancer drug abiraterone, which was approved for use by the NHS in 2012. Professor Workman also led the ICR teams that in partnership discovered the leading inhibitors of HSP90 (AUY922) and PI3 kinase (GDC-0941) which are now undergoing clinical trial. In recognition of their productivity success in drug discovery and development, Professor Workman’s team received the prestigious American Association of Cancer Research Team Science Award in 2012.

About The Institute of Cancer Research

The Institute of Cancer Research, London, is one of the world’s most influential cancer research institutes.

Scientists and clinicians at the ICR are working every day to make a real impact on cancer patients’ lives. Through its unique partnership with The Royal Marsden NHS Foundation Trust and ‘bench-to-bedside’ approach, the ICR is able to create and deliver results in a way that other institutions cannot. Together the two organisations are rated in the top four cancer centres globally.

The ICR has an outstanding record of achievement dating back more than 100 years. It provided the first convincing evidence that DNA damage is the basic cause of cancer, laying the foundation for the now universally accepted idea that cancer is a genetic disease. Today it leads the world at isolating cancer-related genes and discovering new targeted drugs for personalised cancer treatment.

As a college of the University of London, the ICR provides postgraduate higher education of international distinction. It has charitable status and relies on support from partner organisations, charities and the general public.

The ICR’s mission is to make the discoveries that defeat cancer.

For more information and interviews contact Claire Bithell in The Institute of Cancer Research press office on 020 7153 5132 or email press@icr.ac.uk.

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Last updated: Sunday, 17 March 2013