New ‘Parp inhibitors’ could prevent certain tumours appearing

Sue Hayward was first diagnosed with ovarian cancer in 2017. Doctors acted swiftly and she was given a hysterectomy followed by sessions of chemotherapy.

But her cancer returned within a year. “I carry a mutated version of a gene known as BRCA1 which makes me susceptible to breast and ovarian cancers,” said Hayward, who works at the John Radcliffe Hospital, Oxford. “It runs in families. My mother died of cancer and we assume her mother did as well.”

This time doctors turned to a new weapon in their anti-tumour armoury. After decades of research – much of it carried out in the UK – scientists have developed a range of drugs known as Parp inhibitors. “I was given more chemotherapy and then put on a daily regimen of a brand of Parp inhibitor pills known as olaparib. I have been clear of cancer ever since,” Hayward told the Observer last week.

Nor is her story unique. Across the UK, increasing use of Parp inhibitors has raised hopes that many individuals susceptible to certain familial cancers can be treated simply and effectively in coming years. Indeed, it may be possible one day to use Parp inhibitors not just to treat patients after cancers appear but to prevent them from developing at all.

“Effectively, Parp inhibitors would be used as a preventive medicine to stop certain tumours from ever appearing,” said Professor Herbie Newell, of Newcastle University. “We will have moved the battle against cancer on to a new footing.”

Parp is short for poly adenosine diphosphate-ribose polymerase, an enzyme that is found in all our cells where it plays a key role in helping cells repair damaged DNA. A Parp inhibitor works as an anti-tumour treatment by stopping a cancer cell’s own Parp enzyme from doing its repair work and so causes it to die.

“Unravelling the way that the Parp enzyme helps cells repair themselves led to the discovery of chemicals that could disrupt this process. This was the result of decades of basic research work in biology laboratories across the UK and that is what has led us to these new drugs,” said Newell.

The clinical evaluation of the first Parp inhibitors began 20 years ago just as the funding charity Cancer Research UK (CRUK) was formed out of an amalgamation of the Imperial Cancer Research Fund and the Cancer Research Campaign. Since then the organisation has played a key role in funding research in the field.

“Essentially we have found the achilles heel of tumour cells and have learned how to use that information to destroy them,” said cancer expert Prof Steve Jackson of Cambridge University. His team of researchers – backed by CRUK funding – played a key role in the discovery and development of the Parp inhibitor olaparib.

This work followed on from earlier research in the US and the UK that had revealed the existence of two genes – Breast Cancer 1 and Breast Cancer 2 (BRCA1 and BRCA2 gene) – which have mutated versions that increase a carrier’s risk of getting a number of cancers, including those of the breast, ovary and prostate. Each can be inherited from either parent and can spread through lineages with devastating effect.

It is estimated that in the UK there are tens of thousands of people who carry pathogenic versions of the BRCA1 and BRCA 2 genes. For these individuals, the development of Parp inhibitors offers the prospect of protection against the raised cancer risks that they have inherited.

“When we first developed Parp inhibitors we gave them to patients who were in the late stages of their cancers,” said Jackson. “They had nothing to lose. We were not sure what to expect but found there were quite a number of patients who responded quite profoundly.”

Today, Parp inhibitors are being given earlier and earlier to cancer patients. “We are also seeing that a substantial fraction of these patients are surviving long term,” added Jackson. “One lady that I know, who was in late-stage cancer, started taking a Parp inhibitor nearly nine years ago and is now absolutely symptom-free.”

And it is this progression to earlier administration of the drug that is now encouraging scientists to consider the use of Parp inhibitors such as olaparib in a preventive role. Individuals from families affected by mutated BRCA genes would be given these drugs before they had developed cancer.

This could have considerable benefits. At present, women from affected families sometimes elect to have mastectomies or hysterectomies to prevent the onset of inherited breast or ovarian cancer. Regularly taking Parp inhibitors might prevent the need for such operations.

“However, there are side effects involved in taking these drugs and it is now a matter of ongoing research to work out how we might balance the risk of those side effects with the potential benefit of preventing tumour development in the first place,” added Newell. “That is exactly the research question that is currently being addressed.”

For her part, Sue Hayward said she had felt fatigued after taking the drug. “But I’ve become accustomed to it. At the end of the day, I just feel lucky that I have had access to a medicine like this.”