Identifying active targets in hard to treat cancers

Dr Geoff Macintyre and Dr Anna Piskorz have received a Cancer Research UK Innovation Prize to develop a test that could identify active therapeutic targets in hard to treat cancers.

Over the last 40 years, improvements in prevention, detection and treatment have revolutionised cancer medicine and survival has doubled. However, progress has not advanced equally for all forms of the disease. Several cancers such as lung, pancreatic, oesophageal, ovarian and brain tumours share poor five-year survival and have realised only limited improvement in the past decade.

DNA in normal human cells is packaged into two pairs of 23 chromosomes. But in some hard to treat cancers, this number can change over time – a process called chromosomal instability. This makes the cells in a tumour incredibly diverse, which may help them promote tumour spread or contribute to cancer drug resistance.

Chromosomal instability can also make it harder to identify targets for therapy as many genes are affected within the tumour. In these cases, using a standard personalised therapy sequencing test will identify 10s to 100s of potential targets for treatment, whereas in reality only a handful of these targets could be used to find a treatment.

Dr Geoff Macintyre and Dr Anna Piskorz from the Markowetz and Brenton Groups have developed a test that hopes to make sense of this chromosomal instability, identifying a small number of targets to predict which treatments a patient is likely to respond to.

Research by the team, published last year in Nature Genetics, found different types of chromosomal instability leave tell-tale patterns in the DNA. They developed computational methods to translate these patterns into signatures which can predict overall survival and tumour progression.

By applying this approach to 500 ovarian cancer patients, the researchers identified 7 different signatures of chromosomal instability. These signatures allowed the researchers to identify the pathways causing the chromosomal instability which can then inform therapy selection.

In standard tumour sequencing, the DNA of all cells in a sample is combined and sequenced, giving a readout of all the types of chromosomal instability that have happened in the life history of the tumour.By using single cell DNA sequencing, Dr Macintyre and Dr Piskorz get a readout of the process that is actively altering the DNA with a tumour. This active signature in the sample could then inform the best treatment.

Dr Macintyre and Dr Piskorz have been awarded a £50,000 Innovation Prize from Cancer Research UK to take this test further and carry out a retrospective clinical trial. Currently in the UK, if the first treatment doesn’t work, ovarian cancer patients are given a choice between two chemotherapy drugs: doxorubicin or gemcitabine. In this retrospective clinical trial, the team hope to demonstrate their test can correctly predict patients’ responses to doxorubicin.

If successful, the next steps would be to make this test available to patients with ovarian cancer and apply for funding to carry out clinical trials for other therapies. The team are currently studying a set of over 12,000 cancers to find new signatures which will allow prediction of therapy response across multiple tumour types. If successful, their test has the potential to make precision medicine a reality for the many hard to treat cancers.