Investigating mechanisms of hormone resistance in advanced prostate cancer using new models based on stem cell culture

Background to the project

The androgen receptor is a key driver of prostate cancer growth that remains active despite hormone therapy in advanced treatment resistant prostate cancer. Embryonic stem cells have special properties that are shared with cancers, such as being able to multiply indefinitely and more rapidly than normal cells.

Previous research has shown that genes essential for these stem cells properties are also found in prostate cancer. Researchers can use special culture methods to induce the expression of these stem cell characteristics within prostate cancer cells grown in the laboratory, mirroring the pattern seen in patients with advanced cancer.

What they set out to do

Professor Robson’s research team set out to improve understanding of how advanced prostate cancer becomes resistant to hormone therapy. They planned to look at what happens to the androgen receptor, which is a key driver of prostate cancer growth, when hormone resistance sets in. They planned to do this using special stem cell culture methods to induce the expression of key stem cell proteins within prostate cancer cells grown in the laboratory and so mirroring the patterns seen in patients.

Their work looked to explore how the stem cell environment affects the androgen receptor and its action, which they hoped would shed new light into ways of blocking androgen receptor activity. They planned to do this using human cell lines, which had been maintained long term in the laboratory, as well as fresh human prostate cells cultured directly from clinical material, to ensure that the findings are as faithful as possible to patients’ biology.

What they found out

By inducing the expression of certain stem cell proteins within prostate cancer cells grown in the lab to match their expression in patients with advanced prostate cancer, the researchers found an association between high levels of certain key stem cell proteins and poor survival and resistance to treatment. They then looked at how these proteins and their environment can drive cancer growth through the androgen receptor. Contrary to their initial expectations, the scientists found out that the cancer cells were bypassing the androgen receptor and driving cancer growth in a different way. This work has helped to identify new potential targets for the treatment of advanced prostate cancer patients. They now need to look at whether blocking these targets can stop prostate cancer growth and they’re looking for further funding to help them do this.

How this will benefit men

This project has helped Professor Robson’s research group understand why patients whose advanced prostate cancer displays certain protein expression patterns may be resistant to therapy, and helped identify new potential targets for treatment. The finding that certain stem cell markers are associated with worse clinical outcomes could at some point inform the design of a clinical trial to help identify those patients at highest risk of developing incurable disease.

Grant information

Institution - Newcastle University
Researcher - Professor Craig Robson
Grant award - £209,648
Duration - 2013-2017
Reference - PG12-24 Robson