Crashing cancer’s backup system – our progress so far

With the phrase often touted by the media, it can be difficult to keep track of the ‘next big thing’ in cancer treatment.

PARP inhibitors are a relatively new type of cancer drug that have been branded as such. And not without reason.

These drugs exploit genetic weaknesses in cells by preventing the cells from fixing fatal faults in their DNA. The drugs are also the culmination of more than two decades of slog by Cancer Research UK-funded scientists and others.

And while the process of bringing drugs from the lab to the clinic is never plain sailing, the ongoing endeavour with PARP inhibitors is continuing to prove an exceedingly fruitful one.

Researchers funded by us brought the first ever PARP inhibitor – rucaparib – into the clinic in 2003. And another drug, olaparib (Lynparza), has been approved in Europe and the US as a treatment for ovarian cancer patients with certain faulty genes. Our scientists were involved throughout this drug’s development, from laying the initial foundations in the lab to testing it out in patients.

Both of these drugs are now being looked into as a treatment for a number of types of cancer, and across the globe researchers at various institutions are bringing a handful of other PARP inhibitors through various stages of clinical development.

Clearly this is a buzzing area of research, but where are we now in the drugs’ developmental journey? And how did they come about in the first place?

A brief history of PARP

PARPs, or poly ADP-ribose polymerases, have been on scientists’ radars since the ‘60s. Yet it wasn’t until midway through the 2000s that they began to send ripples of excitement through the cancer science community.

Both BRCA and PARP molecules repair faults in our DNA

The decade before, an international search headed by our scientists found two genes that would become key to the field of cancer biology – BRCA1 and BRCA2.

These genes fix potentially harmful faults in our DNA code. But when BRCA genes are faulty, cells can’t repair their DNA properly – a vulnerability that leaves a person at greater risk of developing cancer, particularly breast, ovarian and prostate.

Just as we would be lost without a backup system for our precious computer data, cells have other mechanisms that can swoop in and take over the repair job. And that’s precisely what PARP molecules do.

So scientists began to wonder whether blocking this backup system in cancer cells carrying faulty BRCA genes would leave them susceptible to a fatal accumulation of DNA damage. And in 2005, that’s what two seminal studies, published back to back by our researchers in the journal Nature, showed – blocking PARP in cells that already had BRCA faults made the cells die.

The dawn of PARP inhibitors

With no time like the present, the race was on to translate these findings into the clinic. But even before this excitement was sparked, our scientists had already sniffed out the potential of PARP inhibitors, and investigations for one candidate – rucaparib – were already underway.

“I wrote the first prescription for rucaparib in 2003, and then we published the first clinical trial investigating the drug, which was funded by Cancer Research UK,” says Professor Ruth Plummer, one of our scientists based at Newcastle University.

“So it was thanks to Cancer Research UK that this class of drugs was first brought into the clinic.”

It was thanks to Cancer Research UK that this class of drugs was first brought into the clinic

– Professor Ruth Plummer, Cancer Research UK

Then in 2008, scientists had another candidate on their hands that could potently block this backup repair system. This molecule – called KU-0059436 – would go on to become the drug olaparib.

The drug was then ushered into clinical trials looking at patients with advanced breast, prostate, lung and ovarian cancer, which produced encouraging early results. And this was particularly true for women with ovarian cancer caused by BRCA mutations, a discovery that was backed up by larger studies. This led to olaparib’s eventual approval in the US and the UK for these women – although there were a few hurdles along the way.

While these licensing decisions led to much optimism among patients and scientists alike, they also highlight that the journey to these drugs hasn’t been uniform. In particular, the drugs haven’t performed as well as predicted for breast cancer patients with BRCA gene faults, and thus they’re still not approved as a treatment for this type of cancer.

“We don’t know yet why this is,” says Plummer. “It could have something to do with previous treatments that patients received, or that the trials testing the drug [NB14] weren’t selecting the right patients.

“It’s possible that more patients with ovarian cancer have a cancer cell type targetable by PARP inhibitors than those with breast cancer. It’s something that we still don’t understand.”

Undeterred by this, scientists have pushed on and at least five different PARP inhibitors are being put through their paces in clinical trials for breast cancer patients whose tumours carry faulty BRCA genes. One of these trials, testing out the drug rucaparib, is being led by one of our researchers – Professor Judith Bliss, from the Institute of Cancer Research in London.

Rucaparib also performed so well in trials for ovarian cancer that last year it was designated a ‘breakthrough therapy’ by the US Food and Drug Administration (FDA) for patients with advanced forms of the disease.

Targeting hard-to-treat cancers

PARP inhibitors may have been in the limelight for breast and ovarian cancers, but BRCA mutations are also linked to other cancers. From melanoma to prostate and pancreatic cancers, this knowledge opened the floodgates for further research.

Just last year a trial headed by one of our researchers, Professor Johann de Bono from the Institute of Cancer Research in London, made headlines after olaparib was shown to stall tumour growth in men with advanced prostate cancer, most of whom had BRCA faults. But this trial is still underway, so it’s too early to say whether olaparib will have a place in the clinic for this group of patients. That said, other PARP inhibitors, such as veliparib, are also in trials for prostate cancer patients, so it’s clearly a promising area of research.

Another area that’s also looking promising is pancreatic cancer. With survival for these patients changing little over the past few decades, it’s encouraging that researchers are also scrutinising PARP inhibitors for this hard-to-treat cancer.

For example Professor Jeff Evans, one of our researchers based at the Cancer Research UK Beatson Institute in Glasgow, recently launched a trial for pancreatic cancer patients with faulty BRCA genes. He’s combining olaparib with standard chemotherapy drugs and radiotherapy to see if this trio can shrink tumours and make it possible to remove them with surgery.

Patients with another hard-to-treat cancer that shares pancreatic cancer’s poor outlook – oesophageal cancer – may too benefit from PARP inhibitors, something our researchers are also looking into.

Only good for one thing?

While BRCA faults may have been the basis for the development of PARP inhibitors, the drugs’ uses may well extend beyond cancers linked to these genes.

Some tumours have mistakes in genes other than BRCA that are also involved in fixing DNA damage, meaning they share a genetic weakness that can also be exploited by PARP inhibition.

The term ‘BRCAness’ has been coined to describe this characteristic, and scientists soon realised that this widened the playing field for these drugs. This is especially true given that harmful BRCA mutations are actually relatively rare, and since then the list of cancers that PARP inhibitors are being trialled in has steadily grown.

As scientists learn more about the faulty genes involved in cancer, and searching for these in patients becomes quicker and easier, then over time this list will gradually be refined to give a much clearer picture of which patients are most likely to benefit from PARP inhibitors.

Where to next?

While there seems to be a whirlwind of research going on, PARP inhibitors are still relatively in their infancy. So it’s too early to tell whether they’ll find their way into the clinic for all the cancers that they are being trialled for. And even if they do, that does not signal the end of the battle – as with any form of treatment, resistance can develop.

But when cancer fights back, so too can scientists. Our researchers in Dundee have been looking at chemotherapy resistance in ovarian cancer and found that tumour cells can spit out olaparib and rucaparib using the same mechanism that allows them to pump other widely used drugs out of the cell, making the treatment ineffective.

But the team found that this pump can’t regurgitate two different PARP inhibitors – called veliparib and AZD2461 – that they looked at. This offers a glimpse at a potential solution to the problem of resistance in ovarian cancer patients treated with these drugs.

We need to know more about possible drug interactions

– Professor Ruth Plummer, Cancer Research UK

But resistance isn’t the only challenge. “Researchers want to know if PARP inhibitors can safely be used alongside other drugs,” says Plummer. “So we need to know more about possible drug interactions.

“The second major challenge is finding out whether PARP inhibitors can safely be used to reduce the risk of cancer in people with BRCA mutations.

“If they could prevent radical surgery like mastectomies in these individuals, that would be fantastic, but getting the trial design right is tricky.”

Piecing all of this together, PARP inhibitors are clearly a promising area of research that’s gradually bearing fruits.

But there is still some way to go.

And as studies teach us more about the importance of making cancer treatment personal, the need for carefully designed and tested therapies like PARP inhibitors becomes ever more vital.

Justine