Targeting the shape-shifting androgen receptor

Grant information

Reference - AMS15-001
Researcher - Dr Adam Sharp
Institution - Institute of Cancer Research
Duration - 2016 - 2018
Status - Completed
Award - £30,000

Why did we fund this project?

• Prostate cancer needs hormones to grow. These hormones bind to a type of protein on prostate cancer cells called the androgen receptor (AR), which then signals to the cancer cells to grow and spread.
• One type of treatment for prostate cancer, called hormone therapy (or ADT), works by stopping the hormones prostate cancer cells rely on from being produced, thus slowing their growth and spread.
• However, the AR is something of a shapeshifter, and as men are treated with hormone therapy, it adapts to be able to tell cancer cells to grow and spread even without hormones. This shape-shifted version of the AR is known as a splice variant.
• When these splice variants occur in a man's prostate cancer, hormone therapies stop working.
• To shape-shift into its new splice variant form, the androgen receptor needs help from lots of other proteins.
• Dr Adam Sharp and team proposed that if they could identify these helper proteins and stop them in their tracks, they could prevent or overcome resistance to hormone therapies.

What did the team do?

• The team studied prostate cancer cells to learn which proteins help the AR to shape-shift into its splice variant form.
• They then blocked the action of these helper proteins to see if this stopped the splice variants developing.
• The team also studied prostate tissue from men with prostate cancer to see if the helper proteins were more common in men who were resistant to hormone therapies.

What did the team achieve?

• The team successfully identified 3 helper proteins that help the AR shape-shift into its splice variant form.
• They showed stopping these proteins in their tracks slowed down the growth and spread of prostate cancer cells. This suggests that they could be targets for new treatments.
• The team also used specialised computer programs to show these proteins could be targeted by new and existing drugs.

What does this mean for men?

• The team have identified 3 new proteins that help to cause resistance. The team now want to design and develop drugs to target these proteins.
• Targeting these proteins with treatments could provide a new option for men with advanced disease for whom hormone therapy has stopped working. For these men, treatment options are currently limited.