The cancer drug that turned scientific thinking on its head – and became a very British success story

More than 40,000 people worldwide have been treated with the drug olaparib for ovarian, breast, pancreatic and prostate cancers. On its approval for use by drug regulators in 2014, it became the first of a new class of drugs called PARP inhibitors that kill cancer cells by undermining their ability to repair damage to their DNA.

In one clinical trial, almost half of women whose advanced ovarian cancers contained mutations in one of two genes – BRCA1 and BRCA2 – saw no deterioration of their disease five years after being given olaparib. That compares with one in five (48.3% vs 20.5%) for those given a placebo.

Olaparib is a very British success story. It is also one that shows how charities play a bigger role in the development of new medicines than many people realise. Cancer Research UK (CRUK) funded much of the basic research behind olaparib in Cambridge and London, and helped set up a biotech company to develop it, before it was commercialised as Lynparza by the Anglo-Swedish pharmaceutical giant AstraZeneca.

“Without funding from charities like CRUK, there would be no olaparib today,” says Chris Lord, professor of cancer genomics and deputy director of the Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London, who helped demonstrate the drug’s potential.

Olaparib’s origins lie in the 1960s when scientists began piecing together how cells repair damage caused to their DNA by things such as metabolic reactions and exposure to sunlight. The Swedish biochemist Tomas Lindahl, funded from 1981 by one of the two charities that later merged to become CRUK, was jointly awarded the Nobel prize in chemistry for his work on DNA repair in 2015. In 1992, Lindahl co-authored a paper in Nature that identified an enzyme called poly-ADP ribose phosphorylase, or PARP, as a key component of a cell’s DNA repair system, kick-starting research into how the enzyme worked.

It was a field that Steve Jackson, the biologist whose research led to olaparib, found himself exploring through what could be called a scientific twist of fate. During his research on gene transcription, the process through which DNA is copied to produce the instructions to make proteins, he discovered proteins that only became activated in the presence of DNA. Follow-up work revealed that they became activated in response to DNA breakages, suggesting they were part of a cell’s DNA repair system.

Jackson, now professor of biology at the University of Cambridge and head of CRUK’s laboratories at the Gurdon Institute, knew that chemo and radiotherapy worked partly due to cancer cells’ increased susceptibility to DNA damage. He wondered whether targeting their ability to repair this damage, by, for example, finding drugs that could block DNA repair activity, would enhance the effects of existing cancer therapies.

Others however, weren’t convinced. DNA repair defends the body against cancer. “I approached pharmaceutical companies and venture capital groups, but there was no interest,” says Jackson. “They thought my reasoning was counterintuitive. Why would you inhibit something which protects us against cancer?”

He was, however, not alone in his thinking. Researchers at Newcastle University were similarly working to target DNA repair enzymes to enhance existing cancer therapies – in this case, PARP, the enzyme highlighted by Tomas Lindahl in 1992. Faced with the same concerns from potential investors over the risks of tampering with DNA repair processes, both groups turned for support to the charity sector, and to the Cancer Research Campaign – one of the organisations that later merged into CRUK.

With its advice and funding, Jackson set up KuDOS Pharmaceuticals in 1997. Key to its business plan was the concept of “synthetic lethality”. This is the idea that, when a cancer cell contains defects in a particular process, it often becomes reliant on a second “back-up” process to survive – making this second process very sensitive to targeting with drugs. “It’s like chopping one leg off a four-legged table,” says Jackson. “The table will wobble but still just about stay upright. But if you chop off another leg … that’s it. No more table.”

KuDOS began identifying compounds to block the activity of DNA repair enzymes including PARP. Following a chance late-night meeting in a bar at a conference, Jackson began a collaboration with Prof Alan Ashworth, an expert in the BRCA genes and associated cancers at the Institute of Cancer Research, London. The BRCA genes had been identified only a few years earlier, with researchers funded by the Cancer Research Campaign playing a prominent role.

BRCA genes are involved in DNA repair – so if a person inherits faulty, mutated BRCA genes it increases their risk of cancer, especially ovarian and breast cancer. Ashworth’s team, with funding from CRUK, had been working to find ways to kill BRCA mutant tumour cells while sparing healthy cells. Joining forces, Ashworth and Jackson decided to see what happened when BRCA-mutated cells were exposed to KuDOS’s new DNA repair-blocking compounds – including one that targeted PARP. “It was exciting; a bit of a eureka moment,” says Jackson. “The BRCA-deficient cells dropped dead and the normal ones were fine.”

KuDOS swiftly started a clinical trial of this compound, which would later become olaparib, with positive early data leading to the company’s purchase by AstraZeneca in 2005. Regulators in the US and Europe approved olaparib, sold as Lynparza, to treat women with BRCA-mutated ovarian cancers, which had stopped responding to standard therapies, in 2014, and later against some breast, prostate and pancreatic cancers. Meanwhile the Newcastle group, also backed by CRUK, developed their own PARP inhibitor drug, rucaparib, now sold under the name Rubraca, and approved to treat some ovarian cancers.

Unfortunately, tumours can develop resistance to treatments – even sophisticated, targeted drugs such as PARP inhibitors. In 2008, Ashworth’s group showed that BRCA2-mutated cancer cells, unexpectedly, could “reverse” these mutations, reactivating their defective DNA repair systems and so becoming insensitive to PARP inhibitors. Many other mechanisms of resistance to the drugs have since been discovered.

Lord has spent many years working to find ways to prevent resistance to PARP inhibitors, and to treat patients in whom that develops. In June, he published details of a prototype drug that could block the activity of a DNA repair enzyme called POLQ, and so shrink BRCA-mutated tumours in rats. Early research suggests it can target cancers that are resistant to PARP inhibitors.

Lord’s group has also shown how a similar approach can be used to tackle tumours with defects in DNA repair genes other than BRCA, including two called ARID1A and E-cadherin. “The original work on PARP inhibitors helped us to see how we can use synthetic lethality to target cancers that don’t have BRCA mutations, by exploiting other vulnerabilities,” he says.

Beyond inspiring scientists to find new treatment targets, the olaparib story also highlights the lesser-known roles charities play in driving improvements for patients. “We have a unique part to play because we’re driven by patient benefit rather than profit,” says Michelle Mitchell, chief executive of CRUK. “Based on our expertise, we can back promising but risky science without the need to think about shareholder value.”

Charities are well placed to bridge the gap between university researchers making potentially life-saving discoveries and pharmaceutical companies that are reluctant to back innovations that have limited chances of big returns. “Without the initial funding, we would have been unable to do the basic science or to then get over the barriers to setting up a company,” says Jackson. “Without CRUK, we would not have olaparib.”

Some cancer charities have become better at making use of commercial opportunities that arise from their funding roles. Obtaining patents makes returns on investments and attracting commercial partners possible. More than 60 companies have been started based on CRUK-funded research. The charity currently has more than 30 drugs in clinical and preclinical development, and has supported 11 drugs to market through commercial partnerships.

Between 2013 and 2017, CRUK also licensed more oncology intellectual property (IP) than any organisation in the world other than the MD Anderson Cancer Center at the University of Texas in Houston. This more commercial focus is paying dividends. The charity’s income from intellectual property and royalties, including from olaparib and rucaparib, rose from £62m in 2015 to £100m in 2019.

One of CRUK’s key ambitions is to increase the proportion of people surviving their cancer in the UK from around half in 2010 to three-quarters in 2034. Its growing commercial success is making this more likely thanks to a virtuous circle which sees profits from drug sales being ploughed back into funding research to find new treatments.

“Supporting entrepreneurship, commercialisation and protecting intellectual property generated through the research we fund are important parts of how we can improve cancer survival and outcomes,” says Mitchell, pointing out that PARP inhibitors are transforming treatment for many patients with cancer. “Thanks to our IP, the story of these drugs gets even better as we get royalties from its sales which we can then reinvest in new research.”

To find out more about Cancer Research UK’s work, visit cruk.org, or to donate and fund more life-saving discoveries, go to cruk.org/donate

Comments are closed.