Why do prostate cancers stop responding to hormone therapy?

For people with advanced prostate cancer, hormone therapy can slow the disease and extend life. But for many, the cancer eventually finds a way to resist treatment leaving patients facing uncertainty and fewer options.

Dr Luke Gaughan and his team have had their work on prostate cancer, supported by PCR, published in two papers in the Journal of Clinical Investigation. Their research has revealed a new protein target that could offer hope of new treatments and insight into why some advanced prostate cancers still respond to treatment

We are incredibly proud of what Dr Luke Gaughan and the team have achieved during their time with PCR. This research lays the groundwork for new drugs that could block the production of androgen receptor variants (ARVs) helping to prevent resistance to hormone therapy and improve outcomes for people with prostate cancer.

Hormone therapy is one of the main treatments for prostate cancer but it will stop working for nearly all patients. Hormone therapy works by stopping the androgen receptor (AR) from telling cancer cells to grow. The outside of the AR acts as a switch. When the switch is on, the AR tells cancer to grow. The switch is turned on by male hormones and turned off by hormone therapy.

A major reason for treatment resistance is the production of shortened versions of the AR called androgen receptor variants (ARVs). ARVs don’t have a switch so they are always on and it means that hormone therapy can’t work on them.

Dr Luke Gaughan and his team were exploring how ARVs are made and how to stop this process. If we could prevent the production of ARVs then we could keep hormone therapy working for longer and for more patients.

The team discovered a protein called TRA2B plays a key role in the production of ARVs and in particular one called AR-V7 which stays active during hormone therapy.

The researchers found that when TRA2B levels were high, prostate cancer cells made more AR-V7, grew faster and patients had worse outcomes. When the levels were reduced or blocked by the researchers in the lab, cancer cells grew more slowly.

Targeting TRA2B could offer a new way to treat men whose prostate cancer no longer responds to current hormone therapy, improve patient outcomes and bring renewed hope to people who have few treatment options.

Treatment-resistant cancers behave in different ways but we don’t fully understand why.

The researchers decided to look at tumour samples from men with advanced prostate cancer and compared those with mutations in the AR gene and those without mutations. They also measured how much AR-V7 each tumour produced and how the men responded to hormone therapy.

They found that men with mutations in the AR gene produced much lower levels of AR-V7, responded better to new hormone therapies, and lived longer than those without mutations. This shows that cancers with AR gene mutations are still dependent on the longer form of the AR and therefore still respond to hormone therapies that target it.

The researchers believe that measuring a person’s AR-V7 levels and checking whether they mutations in the AR gene could help doctors decide which treatments will work best for their individual cancer. This could mean more personalised and effective treatments and mean men can avoid unnecessary side-effects from treatments that won’t work for their cancer.