Making precision medicine even more precise

Grant information

Researcher – Professor Johann de Bono
Institution – The Institute of Cancer Research
Award - £500,327
Status - Complete
Reference - MA-ETNA19-006

Why did we fund this project?

• We previously supported Professor Johann de Bono and team to show that a drug called olaparib is an effective personalised treatment for prostate cancers with certain changes (mutations) affecting a pair of genes called BRCA1 and BRCA2. 
• However, not all prostate cancers with these mutations in BRCA1 or BRCA2 respond equally well to olaparib. Additionally, olaparib can be effective at treating some prostate cancers without these mutations. In this project, Professor de Bono and team wanted to figure out why.
• The team proposed that mutations affecting other genes could be important in determining how well men respond to olaparib. If so, understanding which genes are most important could help better select men who are most likely to benefit from this treatment.
• Some prostate cancers develop resistance to olaparib, and the team also wanted to investigate if certain mutations could be helping this to happen. This could lead to treatments that could be combined with olaparib to stop resistance developing.

What did the team do?

• The team studied prostate cancer tissue and blood samples from men who took part in a clinical trial of olaparib.
• Using these samples, they identified the mutations in each man's prostate cancer, and compared this to information about how well each man responded to olaparib, and whether they developed resistance.
• This allowed them to determine which mutations are most closely linked to olaparib response and resistance.

What did the team achieve?

• The team identified multiple mutations that affect how well men respond to olaparib.
• Excitingly, the team found prostate cancers which lose a gene called RNASEH2B can also respond to olaparib, even without mutations in BRCA1 or BRCA2. This discovery identifies an additional group of men who could benefit from olaparib.
• The team also found prostate cancers often became resistant to olaparib by reversing the mutations in BRCA1 or BRCA2. This suggests combining olaparib with a new drug that can stop cancer being able to reverse these mutations could stop resistance developing and make olaparib work for longer.

What does this mean for men?

• The team have uncovered lots of mutations that influence how men respond to olaparib, and how resistance develops.
• They identified one particular mutation that can make prostate cancers without BRCA1 or BRCA2 mutations sensitive to olaparib. This finding could lead to more men benefitting from this treatment.
• The team have also identified new targets for combination therapies that could make olaparib work for more men, and for longer.
• The next step is to further investigate how olaparib can be combined with other treatments, to identify the best combinations to test in clinical trials.