The 2015 Nobel Prize for Chemistry was announced in Sweden last week, and this year went jointly to three eminent researchers, including Dr Tomas Lindahl who works in the Francis Crick Institute.
Nobel Prizes are like the Oscars of the science world. To win a Nobel Prize in chemistry, medicine or physics is the ultimate recognition of a scientist’s contribution to their field and the greatest plaudit a scientist can achieve in their career.
This year’s Nobel Laureates provided fundamental insights into how cells function by uncovering the molecular mechanisms that repair DNA – knowledge which has been critical to our understanding of cancer.
DNA is replicated extraordinarily faithfully whenever cells divide, but sometimes mistakes do occur, and exposure to the likes of radiation or carcinogens can also lead to mutations. Mutated DNA is the fundamental cause of cancer.
Dr Lindhal’s Nobel Prize winning research showed that the rate of DNA damage in cells is so high that there must be mechanisms to repair these mistakes. He discovered a process called base excision repair, which cells use to fix single-strand breaks in their DNA.
It is this repair mechanism discovered by Dr Lindahl which scientists here at The Institute of Cancer Research are exploiting to treat cancer, through an approach called synthetic lethality – where drugs take advantage of a specific weakness in tumour cells.
Dr Chris Lord, Team Leader in Gene Function at The Institute of Cancer Research, London, said: “This Nobel Prize announcement is great news for the field and recognises the importance of DNA repair, both as a normal process but also as a process that is often dysfunctional in diseases such as cancer. Some of the seminal work that the recipients carried out has informed our understanding not only of cancer biology but also how we treat the disease.”
In 2005 we identified a synthetic lethal relationship between drugs called PARP inhibitors and tumours with mutations to the genes BRCA1 and BRCA2, as this feature explains.
BRCA1 and BRCA2 are important for repairing double-strand breaks in DNA, and mutations in these genes predispose women to breast cancer and ovarian cancer.
The protein PARP helps to repair single-strand DNA breaks like those studied in Dr Lindahl’s research, so using PARP inhibitors in BRCA-mutated tumours – whose DNA repair toolkits are already faulty – causes the mistakes in their DNA to build up, and sends cancer cells to their deaths.
The beauty of this treatment is that it’s cancer selective, so healthy cells with functioning BRCA genes are left unharmed by the treatment.
Researchers at the ICR and The Royal Marsden NHS Foundation Trust have led important clinical trials of PARP inhibitors showing their effectiveness at fighting cancer. The PARP inhibitor olaparib has now been approved by the European Medicines Agency for women with ovarian cancer who have defective BRCA genes – the first cancer drug in the world to be targeted against an inherited cancer mutation.
It is thanks to the research carried out by Dr Lindahl and others that we’re beginning to open up new approaches to treating cancer, that take advantage of our exquisitely detailed knowledge of how cells repair their DNA.
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