A new drug treatment could help treat breast cancer in women affected by the hereditary form of the disease, two studies show. The findings, published in the journal Nature, show that drugs which target a protein called poly (ADP-ribose) polymerase 1 (PARP1) could be highly effective against tumours in patients with inherited breast cancer gene mutations. In one of the studies, carried out by researchers at the Institute of Cancer Research in London and Cambridge-based Company KuDOS, a PARP-blocking drug selectively killed off tumour cells that had mutations in either the BRCA1 or BRCA2 gene.
Most cases of breast cancer are not inherited, but around 5-10 per cent are due to a gene mutation. Women who have a mutation in either the BRCA1 or BRCA2 gene have a greatly increased lifetime risk of developing breast and ovarian cancer. The proteins made by these two genes are responsible for repairing DNA damage, a process that also involves PARP1. In people who inherit a faulty BRCA1 or BRCA2 gene, if a single cell acquires a mutation in the other, working copy of either gene then it can no longer repair DNA properly - a key step in the development of cancer. The scientists decided to see if by knocking out PARP1, they could inflict even more DNA damage in cancer cells with no working BRCA1/2 genes, and so trigger the self-destruction of these cells. Team leader Alan Ashworth likened this approach to 'removing two legs of a table'. He said that 'removing one leg is damaging but removing two causes the table to fall over'.
The researchers first tested their idea by blocking PARP1 gene activity in order to kill mouse embryo stem cells that lacked working BRCA1/2 genes. They found that cells with no BRCA1 activity were 57 times more sensitive to the drugs than normal cells, while those with no working BRCA2 were 133 times more sensitive. The team then tested their approach in human tumour cells with no working BRCA2 gene, injected into mice, and found that the PARP1 inhibitors killed the tumour cells but left the healthy surrounding cells unscathed.
The second study, carried out by researchers based at Sheffield University, showed similar results using PARP1-blockers to kill tumour cells lacking BRCA2 gene activity. Phase 1 clinical trials based on the new research are set to begin in a few months. The approach could also lead to new treatments for non-inherited forms of breast cancer, say the teams. Such therapies should have fewer side effects than many current anti-cancer drugs, since they do not affect healthy cells. Thomas Helleday, head of the Sheffield group, also suggested that drugs targeting PARP1 could be given as a preventative measure to people with BRCA1 or BRCA2 gene mutations, to stop tumours from developing. Currently, the only way in which such women can substantially reduce their risk is to have both their breasts and ovaries removed, before cancer develops.