Stopping advanced cancer hiding from treatment

2017 John Paynter Research Innovation Award

• Abiraterone and Enzalutamide are two powerful drugs that can be used to control advanced prostate cancer. However, some men won’t respond to these treatments, and when they do work, eventually men become ‘resistant’ to treatment, meaning drugs stop working as the cancer adapts.
• Better understanding how cancers become resistant to these drugs will help researchers develop ways to prevent resistance from happening, ultimately extending the lives of men with advanced prostate cancer.
• A previous project funded by Prostate Cancer UK and led by a member of Johann's team found that an important reason why these treatments stop working is because cancer cells start to produce abnormal proteins, called ‘splice variants’.
• These proteins are used by prostate cancer cells to ‘hide’ from the effects of 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 that it would 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.

• 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.

• The team found that one particular splice factor is very important in the development of treatment resistance.
• They found that men with prostate cancer that is resistant to treatment have far more of this splice factor in their cancer tissue than men who are still sensitive to treatment.
• Using computer databases, they found a drug that could stop this splice factor in its tracks. Excitingly, they found this drug reduces the amount of resistance-causing splice variants that are produced by cancer cells.

• The team identified a splice factor important in the production of splice variants that allow cancer to hide from treatments.
• They demonstrated that using a drug to block this factor could stop splice variants being made.
• This gives the team the evidence they need to move towards developing drugs that can block the splice factor, and 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. Currently we are unable to make cancer cells sensitive to treatment once resistance has developed.
• Developing drugs that can reverse resistance could help control advanced prostate cancer for longer. The team hope that their new discovery will lead to such drugs being developed.
• Clinical trials will then determine how effective the drugs are at reversing treatment resistance in men. If trials are successful, these drugs could become available to men with advanced prostate cancer.