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New drug targeting cancer weakness shows great promise

Scientists at The Institute of Cancer Research and The Royal Marsden Hospital, working with pharmaceutical company AstraZeneca, have completed a Phase I clinical trial demonstrating the promise of a new type of cancer treatment.

The results were announced recently in The New England Journal of Medicine. Patients with inherited forms of advanced breast, ovarian and prostate cancers – caused by mutations in the BRCA1 and BRCA2 genes – were treated with the new drug olaparib (a PARP inhibitor). In more than half of the patients, tumours shrank or stabilized. One of the first patients to be given the treatment is still in remission after two years.

Dr Johann de Bono, one of the Institute of Cancer Research (ICR) scientists who led the AstraZeneca/KuDOS-sponsored Phase I trial held at The Royal Marsden and the Netherlands Cancer Institute, said the positive results confirmed olaparib should be taken into larger patient trials, adding: ‘It’s giving patients who have already tried many conventional treatments long periods of remission, free from the symptoms of cancer or major side-effects’.

The concept behind this new approach is called ‘synthetic lethality’, in which the treatment works in combination with a patient’s own specific molecular defect. Normal cells have several different ways of repairing damage to their DNA; however, BRCA tumours lack one of these pathways. The drug olaparib blocks a different pathway involving the enzyme PARP, and normal cells can recover from this drug because they can use the BRCA genes. When the drug is applied to BRCA tumours, however, they have no way of repairing their DNA, so they simply die. This is why the drug is so effective at killing cancer cells but normal cells seem to be unaffected.

Mutations in the BRCA1 or BRCA2 genes are thought to be responsible for approximately five per cent of breast and ovarian cancers and approximately one to two per cent of early-onset prostate cancers. Women with a BRCA mutation have an up to 85 per cent risk of developing breast cancer and an up to 60 per cent risk of developing ovarian cancer during their lifetime. Men with a BRCA mutation have an up to 15 per cent lifetime risk of prostate cancer. These patients are at high risk of cancer because the genetic fault weakens their cells’ ability to repair any DNA damage.

Cancer cells with the BRCA1 or BRCA2 mutations were the first discovered to be sensitive to PARP inhibitors, but there is evidence that olaparib might be effective in other cancers with different defects in the repair of DNA. These cancers could include some non-inherited breast and prostate cancers and up to half of the most common type of ovarian cancer.

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