The research groups based at the University of Oxford and University of Toronto tested in the laboratory in mice the effects of PARP inhibitor on tumour cells exposed to different levels of oxygen.
During the growth of a tumour, areas of low oxygen occur in cells because the blood vessels supplying the tumour with oxygen are often weak, twisted and inefficient – the most aggressive tumours often have the lowest oxygen levels.
They found that cancer cells with low oxygen levels are sensitive to PARP inhibitors – an experimental group of cancer drugs. The research suggests the drug could be a powerful therapy used on its own or alongside radiotherapy and chemotherapy to treat the most tenacious tumours across all cancer types – not just breast and ovarian cancer as was previously thought.
Dr Ester Hammond, one of the lead authors based at the University of Oxford said: “These results are very exciting. We have discovered that the tumour cells which are most resistant to conventional therapies respond well to PARP inhibitors.
“At the moment PARP inhibitors are being used in trials to treat patients with breast and ovarian cancer caused by faults in their BRCA1 gene – but we have shown in the laboratory that the drug could be effective for treatment of any tumour with reasonably low levels of oxygen – especially the most aggressive tumours.”
PARP inhibitors block PARP, a protein which is part of DNA’s ’emergency repair kit’ in cells – it prevents mistakes being passed on to daughter cells when cells grow and divide. An alternative ‘repair kit’ is also controlled by the BRCA1 gene – which is often damaged in breast cancer cells. When both copies of the BRCA1 gene are damaged, the cells rely on the PARP pathway to repair cell damage.
The PARP repair kit alone isn’t fully effective so mistakes are replicated when the cell divides and grows – leading to cancer. But, by blocking PARP the cell is no longer able to ‘muddle on’ – it can no longer repair any damage. The cell cannot replicate and it dies.
Healthy cells are unaffected if PARP is blocked because they either contain one or two working BRAC1 genes which do an effective repair job.*
Dr Lesley Walker, Cancer Research UK’s director of cancer information said: “It is very encouraging to see promising new cancer treatments like PARP inhibitors coming out of clinical trials and our drug development programmes. And it’s really exciting that new research like this shows that the drug could work in many cancers – particularly some of those which are most difficult to treat.”
“Cancer Research UK has funded research into PARP inhibitors and their potential use in the clinic since the 1990s, and as part of our focus we are funding a separate PARP inhibitor trial in seven UK centers, of treatment for women with advanced breast or ovarian cancer caused by BRCA1 or BRCA2 gene faults.”
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*The research done in collaboration with Professors Bristow and Helleday showed that low oxygen levels in tumour cells shuts down the BRCA1 repair toolkit. So if scientists also block the PARP emergency repair kit, the cell can not repair any damage and dies – preventing cancer development.”