Targeting The Great PTEN-der

This project will investigate the underlying biology, safety and clinical benefit of a potential new treatment for advanced prostate cancer. The researchers will also investigate whether this treatment works particularly well for men with a mutation in a gene called PTEN, whose usual job is to prevent cells growing out of control.

Research has begun to deliver new ways to treat advanced prostate cancer in recent years, but we still do not have enough weapons in our arsenal to beat it. In the next ten years, real progress is likely to rely on us understanding exactly what underlying biology is driving different types of prostate cancer so that we can tailor treatment.

A common genetic change in men with advanced prostate cancer is a mutation in a gene called PTEN, whose usual job is to prevent cells growing out of control. Men with a fault in this gene often find that treatments like abiraterone and enzalutamide don’t work very well for them. This team will investigate a potential new treatment for PTEN-mutated prostate cancers.

In mouse models of prostate cancers missing PTEN, one of the lead scientists has shown that high levels of a type of cell called Myeloid Derived Suppressor Cells (MDSCs) can block the immune system from trying to fight the cancer and promote therapy resistance.

This seems to hold true in men with prostate cancer too. Doctors have also found high levels of MDSCs in some men with advanced prostate cancer who aren’t doing well on treatments like abiraterone.

The researchers will combine laboratory and clinical work; first testing what happens to the immune response, cancer cell growth, overall tumour size and eventual survival when they use a drug to stop MDSCs infiltrating prostate cancers in mice. They will also investigate whether treating the mice with abiraterone at the same time makes any difference to how well this new type of treatment works.

While they are doing this work to understand the basic biology of the drug and how it works, they will also conduct a phase I safety trial to test how safe this drug is for men. They’ll then run a bigger study to see whether treatment with this new drug can enhance the effect of enzalutamide in men with advanced prostate cancer, so it works better for them for longer.

Throughout these clinical tests, the research team will collect blood and biopsy tissue from the patients, so that they can look back to see whether the men who respond best to the combination of enzalutamide and the new drug are those patients with a mutation in the PTEN gene. This would imply that this combination would be an appropriate first choice for these men.

Finding the right drug for the right man at the right time is an important part of our new ten year research strategy. Studies like this that aim not only to develop new treatments, but also to hone that treatment into a precise tool to work out the men who are most likely to benefit, will be key to realising this ambition.

Reference - RIA15-ST2-018
Lead Researchers - Professor David Waugh and Professor Johann de Bono
Institution - Queen’s University Belfast
Award - £819,364