Wednesday 9 June 2010
A mutation present in around half of malignant melanomas has been confirmed as a strong drug target, according to research published today in Science Translation Medicine. The study was conducted by The Institute of Cancer Research (ICR) and funded by the Wellcome Trust, Cancer Research UK and the ICR.
Several drugs that target the BRAF mutation have already reached clinical trial in patients with this deadly form of skin cancer, and some are showing promising results. However, it has not been clear whether their effectiveness was from inhibiting BRAF as designed or for another reason. In addition, the first drug to be trialed in melanoma patients, sorafenib, was last year halted during Phase III testing after it failed to show a survival benefit, adding uncertainty over the importance of damaged BRAF in such cases.
To determine how these drugs were working, Professor Richard Marais and colleagues at the ICR constructed models using drug-resistant forms of the BRAF protein. They then tested whether the drugs retained their anti-cancer activity on tumour cells with these damaged proteins.
These studies show that sorafenib, a first-generation drug, does not work in melanoma because it does not target the damaged form of BRAF in tumours, whereas a second-generation drug called PLX4720 works in melanoma because it does target damaged BRAF.
Professor Marais says: “We have absolutely confirmed that BRAF is an important drug target for malignant melanoma, and that the clinical benefit from these second-generation drugs is due to their ability to target the damaged BRAF protein. It is crucial that we understand the mechanism behind these drugs’ effects to ensure they are only given to patients with the specific genetic defects – in this case, a mutated BRAF gene – that will allow them to benefit. This knowledge may also help us combat resistance and develop new-generation drugs.”
Around 10,000 people are diagnosed with malignant melanoma each year in the UK, and around 2,300 die as the disease is difficult to treat once it has spread to other organs.
BRAF-targeting drugs may also be important in other tumour types, as mutations in this gene are common in thyroid cancer (45 per cent of cases), ovarian cancer (10 per cent), and colorectal cancers (13 per cent).
Dr Simon Vincent, Cancer Research UK’s head of research funding, said: “Results like this are so exciting because they confirm the potential of the new approach to cancer therapy. Decades of work unpicking cancer’s genetic weaknesses, and trying to turn this knowledge into treatments that can target them, are now finally bearing fruit.
“Melanoma is a cancer that can spread rapidly, and is notoriously hard to treat. Now we know that specific mutations within some melanomas can be precisely targeted, we can push forward with clinical trials to reap the benefits of this new technology.”
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The Institute of Cancer Research (ICR)
- The ICR is Europe’s leading cancer research centre
- The ICR has been ranked the UK’s top academic research centre, based on the results of the Higher Education Funding Council’s Research Assessment Exercise
- The ICR works closely with partner The Royal Marsden NHS Foundation Trust to ensure patients immediately benefit from new research. Together the two organisations form the largest comprehensive cancer centre in Europe
- The ICR has charitable status and relies on voluntary income, spending 90 pence in every pound of total income directly on research
- As a college of the University of London, the ICR also provides postgraduate higher education of international distinction
- Over its 100-year history, the ICR’s achievements include identifying the potential link between smoking and lung cancer which was subsequently confirmed, discovering that DNA damage is the basic cause of cancer and isolating more cancer-related genes than any other organisation in the world
For more information visit www.icr.ac.uk
The Wellcome Trust
The Wellcome Trust is a global charity dedicated to achieving extraordinary improvements in human and animal health. It supports the brightest minds in biomedical research and the medical humanities. The Trust's breadth of support includes public engagement, education and the application of research to improve health. It is independent of both political and commercial interests.
For more information visit www.wellcome.ac.uk
Cancer Research UK
- Cancer Research UK is the world’s leading charity dedicated to beating cancer through research.
- The charity’s groundbreaking work into the prevention, diagnosis and treatment of cancer has helped save millions of lives. This work is funded entirely by the public.
- Cancer Research UK has been at the heart of the progress that has already seen survival rates double in the last thirty years.
- Cancer Research UK supports research into all aspects of cancer through the work of more than 4,800 scientists, doctors and nurses.
- Together with its partners and supporters, Cancer Research UK's vision is to beat cancer.
For further information about Cancer Research UK's work or to find out how to support the charity, please call 020 7121 6699 or visit www.cancerresearchuk.org