NCRI Cancer Conference 2009 – Bigger benefits from PARP inhibitors

Professor Alan Ashworth is finding new uses for PARP inhibitors

There was a big buzz at the conference about PARP inhibitors. They’re a new class of cancer drugs currently undergoing early clinical trials. And there’s some really clever science behind them, which Kat has blogged about before.

But so far the excitement has been limited to a relatively rare group of patients with breast, ovarian or prostate cancers, whose tumours are caused by inheriting a faulty BRCA gene.

On day 2 of the conference, Professor Alan Ashworth from The Institute of Cancer Research presented the latest research into PARP inhibitors. His exciting news is that there could be many more patients who could benefit from these potential new drugs than previously thought.

Testing the theory

A few years ago, Professor Ashworth teamed up with Cancer Research UK-funded scientist Professor Steve Jackson, whose company KuDOS was making molecules that could block DNA repair processes in cells – including repairs involving a protein called PARP. Some impressive experiments showed that cancer cells with faulty BRCA genes grown in the lab were many times more sensitive to the cell-killing effects of PARP inhibitors than healthy cells.

The same exciting discovery was also made simultaneously by Cancer Research UK’s Professor Nicola Curtin at Newcastle Univeristy, in collaboration with Professor Thomas Helleday then at Sheffield University.

Partly thanks to this work, Professor Ashworth recently received a Lifetime Achievement Award from the European Society for Medical Oncology.

This connection quickly led to early clinical trials of PARP inhibitors in patients with breast and ovarian cancer caused by faulty BRCA genes – including one being funded by Cancer Research UK in Newcastle, and one run by The Institute of Cancer Research.

Professor Andrew Tutt from Guy’s Hospital in London presented encouraging results from one of these trials later on the same day of the conference. His team tested a PARP inhibitor called olaparib in 27 women with advanced disease.  The majority responded to the drug – meaning that their tumours shrank in size, and they experienced fewer side effects compared with standard chemotherapies.

New uses for PARP inhibitors

So PARP inhibitors are definitely big news in the research community. But cancers caused by inheriting a faulty BRCA gene are relatively rare. So what’s really exciting is the emerging evidence that they might be effective treatments for other forms of cancer. This could dramatically increase the number of people who could benefit from these new drugs.

Also at the conference was Cancer Research UK-funded Dr Ester Hammond from the Gray Institute for Radiation Oncology and Biology in Oxford. She presented her research showing that PARP inhibitors might work on cancer cells that have low levels of oxygen. This is known as hypoxia, found in many different tumours.

Because hypoxia switches off some of the DNA repair machinery in the cells, Dr Hammond thinks that adding PARP inhibitors (which block a different part of the repair mechanism) acts as a ‘double whammy’, helping to kill the cells.

‘BRCA-ness’

In his talk, Professor Ashworth described cancers that have characteristic hallmarks and behave in a similar way to cancers caused by faulty BRCA genes. He calls this ”having BRCA-ness”. But what cancers have this ‘BRCA-ness’?

Professor Ashworth’s example was a type of breast cancer that doctors describe as ‘triple negative’. These account for around 15 per cent of all breast cancers, are more common in younger women, and are often more aggressive and more difficult to treat than other types of the disease.

So an early clinical trial testing PARP inhibitors in women with this form of the disease has already been carried out in the USA. And although it’s early days, the results are again encouraging and are likely to be followed up in larger trials.

Professor Ashworth also talked about his experiments on cancer cells grown in the lab with faulty PTEN genes. He has found that these are more sensitive to PARP inhibitors than healthy cells – similar to cancer cells with faulty BRCA genes, although not quite so dramatic.

As PTEN is often faulty in many different types of cancer, this widens the door even further for PARP inhibitors. There are now plans afoot to set up clinical trials for people with prostate, womb, and bowel cancers, and melanoma skin cancer who have faulty PTEN genes in their cancers.

PARP inhibitors in combination

So far PARP inhibitors have been tested in early clinical trials on their own. But they’ve also got potential to be used in combination with chemotherapy drugs, where they may prove to have even more impressive effects. But how do doctors prioritise which combinations to test in clinical trials?

Professor Ashworth is currently testing every chemotherapy drug currently in use in combination with PARP inhibitors on cancer cells grown in the lab. This could reveal some powerful new combinations for treating many different forms of the disease in the future.

PARP inhibitors have really exciting potential for treating people with rare breast, ovarian and prostate cancers caused by an inherited faulty BRCA gene. And what’s even more exciting is that their scope is ever-widening to embrace larger groups of patients. There’s certainly a feeling among scientists and doctors that this new class of drugs could have a big impact on people’s lives in the future.

The PARP story is an elegant and excellent example of how years of research into basic cancer biology can – ultimately – translate into new drugs. There’s definitely a feeling at the conference that a lot of hard work is finally paying off – and that there’s more in the pipeline.

Alison Ross, Senior Science Information Officer