It is a story beginning with a global race to hunt down the BRCA2 gene, involving the discovery of an Achilles heel within some cancers and culminating in a revolutionary new approach to cancer treatment. The development of olaparib, which has now been recommended for approval by the European Medicines Agency, was underpinned by two decades of pioneering and at times dramatic scientific discovery here at The Institute of Cancer Research, London.

Back in 1995, Professor Alan Ashworth, one of the ICR’s leading scientists and until recently our Chief Executive, played a key role in the team that identified the BRCA2 gene. Its discovery has had a huge impact on cancer research and treatment. And it paved the way for the unexpected finding 10 years later by Professor Ashworth of a genetic weakness in cancers with BRCA mutations. We are now on the cusp of seeing olaparib – the first in a new class of drugs called PARP inhibitors - take advantage of that genetic weakness to transform treatment of BRCA-mutant cancers.

The story begins with the hunt for the BRCA genes

Scientists had suspected breast cancer ran in families since the 1940s, and were keen to search out the genetic basis for the phenomenon. By the late 1980s, researchers were scanning the human genome for a gene called ‘breast cancer 1’ or BRCA1, and in 1994 - after a frenetic and hugely competitive worldwide search. BRCA1 was shown to be faulty in a number of families affected by hereditary breast and ovarian cancer. But although the gene’s discovery was exciting, researchers soon realised it wasn’t responsible for every case of inherited breast and ovarian cancer.

A few months later, a team at the ICR led by Professor Mike Stratton discovered the location of the second breast cancer susceptibility gene, BRCA2, and then in collaboration with Professor Ashworth’s team, identified the gene itself. Testing for BRCA1 and BRCA2 is now used routinely by health services across the globe to identify women at high risk and advise on preventative strategies.

Across the globe, researchers began studying the BRCA genes, trying to understand the roles they played and how we could use this knowledge in our management of cancer. Scientists now understood that women who inherited faults in either of the BRCA genes had a high risk of developing breast and ovarian cancer, while men were at increased risk of prostate cancer. But exactly what the BRCA genes did in normal cells, and how inheriting faults in them raised the risk of cancer, remained a mystery.

Identifying cancer’s Achilles Heel - the concept of synthetic lethality

The story moved on a few years later, in 1997, back at the ICR. Professor Ashworth’s team -in research funded by Cancer Research UK - discovered that a protein encoded by the BRCA2 gene plays a vital role in DNA repair.

Later, in 2001, Professor Ashworth’s team published a further study funded by Cancer Research UK, the Medical Research Council, Breakthrough Breast Cancer and the Mary-Jean Mitchell Green Foundation. This showed exactly how both normal and mutated BRCA2 functioned. It became clear that people who inherited mutations in BRCA1 or BRCA2 had deficiencies in their system for repairing DNA damage – and that it was this that raised their risk of certain cancers. But Ashworth and his colleagues also spotted an opportunity. They hypothesised that cancer cells that lacked either BRCA1 or BRCA2 function would be highly sensitive to drugs that inhibit poly-ADP-ribose polymerase, or PARP – an enzyme that plays a key role in a second DNA repair pathway.

In 2005 Professor Ashworth – funded by Breakthrough Breast Cancer and the Mary-Jean Mitchell Green Foundation – collaborated with the UK biotech company KuDOS, which had already developed a PARP inhibitor. The research showed that PARP inhibitors were indeed highly effective at killing cancer cells with BRCA mutations, while leaving normal cells relatively unharmed. They realised that normal cells could survive the effects of PARP inhibitors by using the BRCA pathway to repair DNA instead, while BRCA-mutant cancers could not. This approach exploited a concept known as ‘synthetic lethality’ where exploiting a specific weakness in tumour cells can be used to devise new treatments for the disease.

Professor Ashworth says: The story of PARP inhibitors shows how close interaction between scientists here at the ICR, a UK biotech and drug company, NHS hospitals and charitable funding bodies can improve the outlook for cancer patients worldwide.

“PARP inhibitors work by exploiting a weakness in cells with mutations to the BRCA genes, and have been shown to be effective in patients who developed breast, ovarian or prostate cancer after inheriting mutations in BRCA1 or BRCA2. One of their strengths is that they kill cancer cells much more than healthy cells, and so cause fewer side-effects than traditional chemotherapies.”

Soon after identifying the synthetic lethality effects using PARP inhibitors, a series of drug trials were begun which were designed to assess whether the observations made in Professor Ashworth’s laboratory translated into patient responses in the clinic. These early trials were led by Professor Johann de Bono and Professor Stan Kaye at the ICR’s and The Royal Marsden’s Drug Development Unit, and Professor Andrew Tutt, who led a team at Guy’s Hospital. Initially these trials focused on patients with breast, ovarian and prostate cancers carrying BRCA mutations. Despite the fact that each of these patients had undergone several previous rounds of chemotherapy that had failed to keep their cancers in check, a significant number of patients showed profound and sustained anti-tumour responses when treated with olaparib. Importantly, the side-effects in patients treated with olaparib were relatively mild compared with conventional chemotherapy.

Promising results from these early clinical trials led to a series of subsequent trials that reinforced the idea that PARP inhibitors could elicit a profound effect when used in BRCA-mutant patients. On the basis of this body of work, AstraZeneca and a series of other drug companies initiated phase III registration trials for PARP inhibitors in BRCA-mutant patients.

What does the future hold for PARP inhibitors?

With favourable toxicity profiles and powerful results against BRCA-mutant cancers, PARP inhibitors appear to have a bright future ahead.

The European Medicines Agency has now recommended olaparib for approval as a monotherapy for the maintenance treatment of adult patients with platinum-sensitive relapsed ovarian cancer with BRCA mutations.

Right from the start, when the search for the BRCA2 gene began, through to the discovery of drugs that specifically target elements of the gene’s function, the ICR has been fundamental to the PARP inhibitor story. And we are now close to realising the potential of these drugs to treat cancer in a completely new way.