Stopping advanced cancer hiding from treatment

2017 John Paynter Research Innovation Award

Grant Information

Institution – Institute of Cancer Research
Lead Researcher – Professor Johann de Bono
Grant award - £516,492.00
Duration of funding – 2018-2021
Status – Complete
Reference – RIA17-ST2-014

Why did we fund this project?

• Abiraterone and Enzalutamide are drugs that are used to treat advanced prostate cancer. However, these treatments don't work for all men, and eventually stop working as the cancer adapts.
• Better understanding why these drugs stop working could help researchers develop ways to prevent resistance from happening, ultimately helping men live better for longer.
• A previous project funded by Prostate Cancer UK found these treatments stop working in part because cancer cells start to produce abnormal proteins, called ‘splice variants’.
• These proteins are used by prostate cancer cells to ‘hide’ from the drugs, making them resistant to treatment.
• Johann and team predicted that stopping these splice variants from being made would mean that men become sensitive to treatments again, or could even kill advanced prostate cancers outright.
• Because the splice variants are so abnormal, it's difficult to target them directly. Instead, the team targeted the proteins that help to make the splice variants, called 'splice factors'.

What did the team do?

• There are hundreds of splice factors, so first the team had to work out which ones are the most important in causing treatment resistance.
• They did this by studying how these splice factors function in cancer cells, and looked for splice factors that were more common in cells from men with treatment-resistant prostate cancer.  
• Once the team worked out the most important splice factors to target for a new therapy, they used computer databases to see if any of them can be targeted with drugs.

What did the team achieve?

• The team found that one particular splice factor is very important in the development of treatment resistance.
• Prostate cancers that are resistant to treatment had far more of this splice factor than cancers which are still sensitive to treatment.
• Using computer databases, they found a drug candidate that could stop this splice factor in its tracks. Excitingly, they found this drug candidate reduced the amount of resistance-causing splice variants that are produced by cancer cells.

What does this mean for men?

• The team are now looking to develop drugs that block splice factors that could be given to men with advanced prostate cancer to make them sensitive to treatments.
• Many men with advanced prostate cancer develop resistance to the drugs that initially control their cancer.  Developing drugs that can reverse resistance would help these men control their cancer and live better for longer.