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Applying genetic principles to treatment of BRCA-mutant cancers

We applied the principle of synthetic lethality to discover a novel strategy for cancer treatment for patients with BRCA1 or BRCA2 gene mutations.

Breast cancer cells (green) invading through a layer of fibroblasts (red). (Luke Henry / the ICR, 2009)

Photo: Luke Henry, the ICR

We demonstrated that drugs called PARP inhibitors could be particularly effective in BRCA-mutant cancers and, with The Royal Marsden NHS Foundation Trust, helped run clinical trials leading to the first PARP inhibitor being licensed in ovarian cancer.

The PARP inhibitor story began back in the mid-1990s, when a team of researchers at The Institute of Cancer Research – including our former Chief Executive Professor Alan Ashworth and Sir Mike Stratton, now Director of the Wellcome Trust Sanger Institute – tracked down the breast cancer gene BRCA2.

Professor Ashworth turned his lab's attention to how BRCA2 works in the cell. His team discovered that, when functioning properly, BRCA2 helps to repair a specific kind of DNA damage called double-strand breaks. Without it, cells make imperfect repairs, introducing the mutations that can lead to cancer.

Solving the problem

Professor Ashworth got to thinking about how BRCA2 might be targeted therapeutically. Many modern targeted cancer drugs work by blocking overactive processes that drive cancer — a hard enough problem. Targeting processes that are underactive, such as DNA repair, can be even more difficult.

The breakthrough came from a conversation between Professor Ashworth and Professor Steve Jackson, who ran a company in Cambridge, KuDOS (later acquired by Astra Zeneca), which was developing drugs to target a DNA repair protein called PARP.

Professors Ashworth and Jackson each realised that the other had the missing part to their own puzzle: cells could stumble on with just one of BRCA or PARP, but should not be able to survive if both DNA repair systems were switched off. That’s because while a little DNA damage can send cells on the path to becoming cancerous, there comes a point when the damage is overwhelming and cells shut down.

Traditional chemotherapies and radiotherapy work on exactly this principle, by causing so much damage to the DNA of cancer cells that they die.

Synthetic lethality

The new strategy was a good example of ‘synthetic lethality’, a concept that emerged from the study of fruit flies in the 1940s.

Two genes are synthetically lethal when a defect in either one of the genes does not obviously affect a cell but defects in both causes cell death. In this particular case, tumour cells can survive mutations in BRCA1 or BRCA2 but when these mutations are combined with a PARP inhibitor, cells cannot cope.

Shortly after Professor Ashworth and Professor Jackson’s conversation, the ICR team quickly got to work and showed that blocking PARP using a drug called olaparib – a PARP inhibitor developed at KuDOS – had a striking effect on cells carrying BRCA mutations.

Clinical trials begin

The ICR team continued to contribute to refinement of PARP inhibitors, working with The Royal Marsden on trials of olaparib.

Some of the early clinical trials using olaparib were led by ICR Clinician Scientists, including Professors Johann de Bono, Stan Kaye and Andrew Tutt.

These clinical trials showed very early on that cancer patients with tumours that carried BRCA gene mutations showed profound and sustained responses to olaparib, vindicating the observations that Professor Ashworth and colleagues saw in the lab.

Subsequent clinical trials have ultimately resulted in olaparib being approved by regulators in the US and Europe for some women with ovarian cancer in late 2014, transforming the outlook for patients with BRCA-deficient tumours.

Research goes on

The Gene Function Team at the ICR, led by Dr Chris Lord, continues to study why different types of tumour cells respond to PARP inhibitors and whether other synthetic lethal effects could also be used to treat cancer.

Olaparib and other PARP inhibitors are still being tested in many more cancer types, and there are even signs that they could work in patients who do have not inherited BRCA mutations, but who do have similar DNA repair defects in their tumours, a concept termed ‘BRCAness’ by Professor Ashworth in 2004.

Meanwhile, the research has come full circle, with scientists back in the lab also learning more about DNA repair from ‘super-responder’ patients who have seen particularly dramatic results with olaparib. And that, of course, is knowledge that could feed into the discovery of new generations of cancer treatments.

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