Targeting cancers’ weak spot: DNA repair mechanisms

The key to developing successful new cancer treatments is to find ways to kill cancer cells while leaving healthy cells unharmed. As cancer cells have inherently unstable genomes, targeting DNA repair mechanisms could be a successful way to treat cancer. 

I heard more about targeting DNA repair mechanisms, and the latest research findings in this area, at a session at the NCRI Cancer Conference in Liverpool. 

Targeting cancer’s Achilles heel 

One of the key themes of the session was how we can develop treatments that selectively target weaknesses inherent in cancer cells – a concept called ‘synthetic lethality’. 

Professor Johann de Bono, Head of Drug Development at the ICR and The Royal Marsden was the first speaker and he told the story of how olaparib – a drug that targets a protein involved in DNA repair – has made the transition from bench to bedside. 

The development of olaparib is underpinned by 20 years of pioneering research at the ICR. In 1995 a team that included Professor Alan Ashworth, then at the ICR, discovered the gene BRCA2. BRCA genes have an important role in repairing DNA breaks that occur in cells, and mutation of BRCA genes can contribute to cancer development. 

Researchers used the synthetic lethality principle to hypothesize that knocking out other cellular DNA repair mechanisms may hit cancer cells disproportionately hard – especially those with BRCA mutations. They targeted the protein, PARP, because it also has an important role in mending DNA breaks. 

Inhibiting PARP in cancer cells that already have BRCA mutations leads to selective cancer cell death. Since BRCA genes are known to have an important role in breast and ovarian cancer, clinicians initially focussed on Olaparib as a treatment for these cancers. Olaparib is now approved for use in ovarian cancer patients who have BRCA mutations in their tumours. 

Using olaparib in other cancers 

Recent research has shown BRCA2 also has an important role in prostate cancer. As a result researchers and clinicians at the ICR and Royal Marsden led an international clinical trial to investigate if olaparib could also benefit men with prostate cancer. 

Professor de Bono presented the positive results of the trial. They found that up to 30% of men with advanced prostate cancer had tumours with defects in their systems for repairing DNA and that patients with these defects responded particularly well to olaparib. The trial is a milestone in cancer treatment as it is the first to show the benefits of ‘precision medicine’ in prostate cancer – where the treatment is matched to the particular genetic characteristics of a man’s tumour.

 Back to the bench – looking to the future

In order for new targeted treatments to be developed we need to understand the molecular mechanisms of DNA repair and how cancer cells acquire high levels of DNA damage. The importance of this approach was emphasised by Dr Aga Gambus from the University of Birmingham, who took the discussion back to the bench, describing her research using frog egg extracts to study proteins involved in DNA repair and replication. Studies like this are vital to identifying new targets, which could lead to new treatments or biomarkers for cancer in the future.

 The session also heard from two further speakers about their different approaches to developing new cancer treatments based on the concept of synthetic lethality.

Dr Thomas Helleday from the Karolinska Institute in Stockholm described another way to target cancer cells with drugs that exploit their impaired DNA repair mechanisms, though research is still at a relatively early stage. 

A potential new type of synthetic lethal approach to cancer treatment was highlighted by Dr Timothy Humphrey of the Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology. He told the audience how inhibiting the checkpoint kinase WEE1 may kill cancers that have mutations in a gene called SETD2. Mutations in SETD2 are frequently found in kidney cancers and some childhood brain cancers making it an attractive target for clinical studies. 

Overall the session was a fascinating journey from the first principles of synthetic lethality, to the development of successful treatments, to glimpses of what the future may hold. Drugs that target DNA repair mechanisms in cancer cells look set to play an important role in cancer treatment in future.