Sidestepping hormone resistance

The team in Nottingham will investigate whether new drugs that block the activity of two proteins that work with the androgen receptor, rather than targeting the androgen receptor itself, can solve the problem of resistance to hormone therapy.

At the moment, one of the main treatment options for prostate cancers that have spread outside the prostate is hormone therapy. This works by stopping the male sex hormone testosterone from binding to and activating the androgen receptor. When it’s ‘turned on’ by testosterone, the androgen receptor is a key driver of prostate cancer growth. Hormone therapy can keep the cancer under control for a while, sometimes for many years. But, eventually – and inevitably for now – the cancer will find a way to continue growing, despite this hormone blockade.

The team will investigate whether bypassing the androgen receptor completely, and targeting its partner proteins instead, can solve the problem of hormone resistance.

They will concentrate on two of these partner proteins (both of which have really catchy names; KDM1A and KDM7A). Their research has four main parts:

  1. To test if levels of KDM7A protein is raised in aggressive prostate cancers. They already know that there are high levels of KDM1A protein in aggressive prostate cancers, and now they want to investigate whether this is true for KDM7A too.
  2. To understand what effect these proteins have on how the androgen receptor behaves, to understand how their interaction might drive cancer growth.
  3. To test what happens to prostate cancer cells grown in the lab when they manipulate the genes that produce these proteins.
  4. To test how well drugs designed to block these two proteins work, and whether they stop androgen receptor activation and cancer growth – particularly in hormone resistant cancer cells.

One of the ultimate aims of our new research strategy is to halve the number of men dying from advanced prostate cancer, and reach a point where men outlive their disease. These drugs are still a long way from being tested in patients, but finding a way to sidestep hormone resistance and keep advanced disease under long term control would be a major step towards achieving this goal. These are the sorts of experiments that will provide the information necessary to take it the next step along the road to the clinic.

Grant information

Reference - RIA15-ST2-005
Researcher - 
Dr Nigel Mongan
Institution - University of Nottingham
Award - £182,871