Sunday 10 February 2008
Cancer cells adapt using Darwin’s ‘survival of the fittest’ principle to resist treatment
"In the struggle for survival, the fittest win out…because they succeed in adapting themselves best to their environment."
Charles Darwin, “The Origin of Species”, 1859
Scientists at The Institute of Cancer Research in London have discovered a new genetic mechanism which helps cancer cells survive by changing the way they respond to treatment. The research, which was jointly funded by Breakthrough Breast Cancer and Cancer Research UK, is published online today in the scientific journal, Nature* and gives us a better understanding of how some cancers may become resistant to treatment.
In 2004, over a quarter of a million people were diagnosed with cancer in the UK, and one in four deaths in the UK are caused by the disease**. The diagnosis and treatment of some cancers is rapidly improving, yet many tumours become resistant to treatment. This common but poorly understood problem is a key reason why treatment fails. Professor Alan Ashworth and scientists at the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research have gained a unique insight into how resistance to certain drugs occurs by identifying a genetic mechanism that can reverse cancer cells’ sensitivity to specific types of treatment, making them become resistant.
Professor Ashworth, Director of the Breakthrough Breast Cancer Research Centre, said; “Drug resistance is a problem common to all types of cancer, yet this important process is poorly understood. Our work has shown how this occurs in some women with cancer and in the future we hope to be able to use this information to predict whether cancer patients will benefit from particular treatments. Furthermore, this information will help us to develop ways of countering the problem of resistance.”
The research was based on studying tumour cells containing a faulty version of the breast cancer gene, BRCA2. Women who inherit this faulty gene are at a much higher risk of developing breast and ovarian cancer. Professor Ashworth’s group demonstrated in 2005 that the cancers these women develop are extremely sensitive to drugs such as PARP inhibitors and the platinum-based chemotherapy drug, carboplatin, that target a weakness in cancer cells arising from this faulty gene. This means that, unlike cells with normal BRCA2 genes, they are unable to repair damaged DNA properly. These therapies are currently being tested in clinical trials for breast and ovarian cancer.
To uncover how cancer cells become resistant to treatment by PARP inhibitors or carboplatin, scientists took tumour cells which contained faulty BRCA2 genes and then made them resistant to both of these treatments. They also studied tumour cells from women with a faulty BRCA2 gene, whose ovarian cancers had become resistant to carboplatin. In both instances, they uncovered a previously unknown genetic mechanism which had altered the faulty BRCA2 gene in the cancer cells, restoring its normal functions and making the cancer resistant to treatment.
This new version of BRCA2 restored the ability of cancer cells to repair genetic damage caused by the anti-cancer drugs, allowing them to survive. Scientists at the Breakthrough Breast Cancer Research Centre believe this particular mechanism of resistance might be a common way by which many other types of cancer become resistant to treatment.
Professor Alan Ashworth adds; “This genetic mechanism works like Charles Darwin’s natural selection theory – it allows cancer cells to survive by changing the way treatments affect them. By understanding this process we can alter patient treatment to counter the problem of resistance.”
Professor Herbie Newell, Cancer Research UK’s executive director of translational research, said: “This research deepens our understanding of why some breast cancer patients with a faulty BRCA2 gene may stop responding to treatment. This type of research is becoming increasingly important as we seek to tailor cancer therapies to individual patients. Although at an early stage, this research may ensure that women are spared unnecessary treatment.”
This research is just one example of the groundbreaking work taking place at the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research, Europe’s leading cancer research centre. One area of the centre’s work is to identify genetic changes that take place in breast cancer cells and use this knowledge to benefit patients in the clinic.
Breakthrough Breast Cancer needs to raise at least £25 million each year for the next three years to support its vital research, campaigning and education work. For more information about Breakthrough Breast Cancer, please visit www.breakthrough.org.uk.
For further information please contact:
The Institute of Cancer Research
0207 153 5359 / 07721 747900
Notes to Editors
* “Resistance to PARP Inhibition Caused by Intragenic Deletion in BRCA2” by Stacey L. Edwards, Rachel Brough, Christopher J. Lord, Rachael Natrajan, Radost Vatcheva, Douglas A. Levine, Jeff Boyd, Jorge S. Reis-Filho and Alan Ashworth.
** CancerStats, CRUK http://info.cancerresearchuk.org/cancerstats/?a=5441
- Professor Alan Ashworth is a world-renowned scientist who was part of the team who discovered the breast cancer gene, BRCA2, in 1995. Women who have inherited a fault in the BRCA2 gene have a greatly increased chance of developing breast and ovarian cancer (and some other cancers).
- Only around 5% of all breast cancer cases are due to inherited faults in known genes associated with breast cancer, such as the BRCA1 and BRCA2 genes.
- In this study, Professor Alan Ashworth and his colleagues at the Breakthrough Research Centre, helped by researchers in the USA, investigated resistance to tailored therapies. They looked at the platinum-based chemotherapy drug, carboplatin, and PARP inhibitors, a potential new treatment for women with a BRCA1 and BRCA2 hereditary breast cancer, which is currently being investigated in clinical trials.
- Carboplatin and PARP inhibitors target cells containing faulty versions of BRCA2. Cancer cells in people with an inherited faulty version of BRCA2 are unable to repair damaged DNA properly. This means that when a tumour is treated with these drugs, which further damage the cells’ DNA, the cancer cells become overloaded with DNA damage and soon die.
- Carboplatin is currently used to treat other types of cancer like lung and ovarian cancer. For breast cancer, previous studies by scientists from the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research, and others working independently overseas, discovered carboplatin was more effective in killing tumour cells with faulty BRCA genes than other standard breast cancer chemotherapy drugs. This is now being investigated in patients in a clinical trial called the ‘BRCA trial’ jointly funded by Breakthrough Breast Cancer and Cancer Research UK.
- In 2005, Prof Ashworth’s group at the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research demonstrated that BRCA-deficient cells are highly sensitive to chemical compounds called PARP inhibitors. PARP inhibitors block another mechanism of DNA repair and are toxic only to cells with faulty BRCA1 or BRCA2 genes. Since then, AstraZeneca and Breakthrough have taken this research forward and are currently undertaking two clinical trials to investigate PARP inhibitors for the treatment of patients with breast or ovarian cancer who have inherited a fault in either the BRCA1 or BRCA2 genes.
- In someone who has inherited a fault in a BRCA gene, PARP inhibitors are predicted to be effective, as the cancers these individuals develop are unable to repair damaged DNA properly. When treated with a PARP inhibitor, the cancer cells become overloaded with DNA damage, and soon die. On the other hand, this treatment seems not to be toxic to normal cells.
- Cancer Research UK is funding a clinical trial using PARP inhibitors in Newcastle and other cancer centres in the UK where women whose breast cancer has been caused by one of the inherited BRCA genes are being recruited to test a new drug.
Breakthrough Breast Cancer:
- Breakthrough Breast Cancer is the UK’s leading charity committed to fighting breast cancer through research, campaigning and education. Our essence comes from the thousands of people who are committed to a single vision - to work for a future free from the fear of breast cancer. More information can be found at: www.breakthrough.org.uk or through the Breakthrough Information Line, 08080 100 200.
- Breakthrough Breast Cancer in partnership with The Institute of Cancer Research has established the UK's first dedicated breast cancer research centre - The Breakthrough Toby Robins Breast Cancer Research Centre.
- The Breakthrough Toby Robins Breast Cancer Research Centre is situated in the Mary-Jean Mitchell Green Building at the Chester Beatty Laboratories at The Institute of Cancer Research. It is the first dedicated breast cancer research facility in the UK and, under the directorship of Professor Alan Ashworth, over 100 scientists and clinicians are working on a programme of cutting-edge biological research to discover the causes of the disease, find methods of prevention and develop new treatments and more effective methods of diagnosis.
Cancer Research UK:
- Together with its partners and supporters, Cancer Research UK's vision is to beat cancer.
- Cancer Research UK carries out world-class research to improve understanding of the disease and find out how to prevent, diagnose and treat different kinds of cancer.
- Cancer Research UK ensures that its findings are used to improve the lives of all cancer patients.
- Cancer Research UK helps people to understand cancer, the progress that is being made and the choices each person can make.
- Cancer Research UK works in partnership with others to achieve the greatest impact in the global fight against cancer.
- For further information about Cancer Research UK's work or to find out how to support the charity, please call 020 7009 8820 or visit www.cancerresearchuk.org
The Institute of Cancer Research:
- The Institute of Cancer Research is Europe’s leading cancer research centre with expert scientists working on cutting edge research. It was founded in 1909 to carry out research into the causes of cancer and to develop new strategies for its prevention, diagnosis, treatment and care. Website at: www.icr.ac.uk
- The Institute works in a unique partnership with The Royal Marsden NHS Foundation Trust, forming the largest Comprehensive Cancer Centre in Europe. This relationship enables close daily contact between research scientists and those on the frontline in the fight against cancer - the clinicians, the carers and most importantly, the patients.
- The Institute is a charity that relies on voluntary income. The Institute is one of the world’s most cost-effective major cancer research organisations with over 90p in every £ directly supporting research.
- Breast cancer is now the most common cancer in the UK, accounting for nearly 1 in 3 of all female cancers.
- Over 44,000 women are diagnosed with breast cancer every year in the UK and 35 women will die every day from this disease.