Around five per cent of bowel cancers are caused by inherited mutations in one of two genes, either MLH1 or MSH2. Cancer cells with these defects can no longer repair DNA damage efficiently, an important step in cells becoming cancerous. But, these same defects expose a potentially fatal weakness for the cancer cells and could be exploited as ‘double agents’ revealing a powerful new way to attack cancer cells and potentially improving treatments for the disease.
The researchers from the Breakthrough Breast Cancer Research Centre at The Institute of Cancer Research (ICR) studied bowel cancers with these mutations. They found that blocking the action of another type of DNA repair protein – called DNA Polymerases – stops MLH1 or MSH2 cancer cells from repairing DNA damage. Unable to repair this damage, cancer cells eventually die.
The scientists propose that targeting cells already carrying one of these mutations with a drug that blocks this second part of DNA repair could be an effective treatment for bowel cancers caused by these mutations. A benefit of targeting just the cancer cells and leaving normal cells relatively unaffected is a reduction in the number of potential serious side effects that are seen with conventional treatments. For example chemotherapy can lower the number of healthy white blood cells, red blood cells and platelets, meaning patients are more likely to get infections, feel more tired than usual or have bleeding problems.
Study author Dr Chris Lord, from the ICR, said: “We’re trying to develop new ways of treating bowel cancer that are based on tailoring the type of treatment to each individual patient. By looking at the patients with defects in two genes called MSH2 and MLH1 we hope to eventually develop new drugs that kill these cancer cells without affecting normal cells.
“MLH1 and MSH2 are a bit of a mixed blessing. They’re clearly linked to the disease but they’re also telling us really useful information about how we can attack cancer cells – they’re a bit of a double agent.”
Bowel cancer is the third most common cancer in the UK, each year more than 37,500 people are diagnosed with the disease. But it is the second most common cause of cancer death in the UK, around 16,000 people die each year of the disease.
People who carry faults in one or both of these genes are more likely to develop hereditary non-polyposis colorectal cancer – accounting for around 1,900 bowel cancer cases each year – these people could benefit from this approach.
Lead author Professor Alan Ashworth, director of the Breakthrough Breast Cancer Research Centre at the ICR, said: “This research uses an approach we pioneered for breast and ovarian cancer patients which is showing great promise in clinical trials. We think we can have the same success with patients whose bowel cancer has been caused by one of these faulty genes.
“We need to identify a drug to exploit this weakness in cancer cells so that we can provide improved treatment for this type of the disease. We are also looking to apply this new approach to other types of cancer and other genetic faults as we move towards tailored treatments.”
Dr Lesley Walker, director of cancer information at Cancer Research UK, said: “These scientists have revealed the mechanism by which these inherited genetic faults in individual bowel tumours could be harnessed into powerful tools to attack cancer cells. The next step is to design drugs that turn this into a realistic treatment option for patients.
“Cancer Research UK has played a pivotal role in funding research to discover and develop treatments based on a similar approach which have already entered clinical trials in patients and are showing considerable promise. It’s very encouraging to see the development of highly targeted treatments tailored to the requirements of individual patients becoming a reality as it offers the opportunity to design new drugs that are truly selective.”
Sarah A. Martin et al (2010). DNA Polymerases as Potential Therapeutic Targets for Cancers Deficient in the DNA Mismatch Repair Proteins MSH2 or MLH1 Cancer Cell : 10.1016/j.ccr.2009.12.046
Notes to editors
Tailored treatment for women with breast and ovarian cancer who have faults in a BRCA gene
About three per cent of breast cancers and around a third of ovarian cancers have a BRCA gene fault. A new class of drugs called PARP inhibitors work by knocking out a key DNA repair mechanism in cancer cells. Cancer cells with a faulty version of the BRCA1 or BRCA2 gene are much more sensitive to PARP inhibitors than normal cells, because their repair system is already compromised. Professor Alan Ashworth was instrumental in developing the approach of targeting defects in DNA repair in cancer. This concept, called synthetic lethality, is now being tested in a variety of clinical trials across the world. If successful, these drugs could be the first tailored treatment for women with an inherited fault in a BRCA gene.