Dr Magali Williamson and Dr Ritu Garg lead our ‘Stopping the spread’ project which focuses on preventing the spreading of the cancer cells by investigating the cellular changes which underpin metastasis. The team recently completed the second year of their five-year PCR project and you can read about this year’s exciting findings below.
The spread of prostate cancer
There are trillions of cells in the human body which are continuously renewing themselves to replace old or damaged tissue. When this renewal process gets out of control and begins to invade healthy tissue, it is called cancer. Cancer cells can break away from their original site, such as the prostate, travel around the bloodstream and settle in other parts of the body, forming ‘metastases’ or ‘secondary tumours.’
Learning more about how and why prostate cancer spreads is hugely important as it could enable the development of a treatment which blocks metastasis and prevents the development of advanced prostate cancer.
What we know so far
Dr Magali Williamson and Dr Ritu Garg are investigating if a protein called PlexinB1 could be one of the answers. PlexinB1 is found in large amounts and is often mutated in prostate cancer cells. When PlexinB1 is activated, there is also an increase in both cell production and movement in prostate cancer. This suggests that it may play a key role in spreading prostate cancer cells. In the first year of the project, the team discovered that PlexinB1 may also play a role in the development of resistance to hormone therapy, one of the main treatments for advanced prostate cancer.
In March last year, labs across the country were forced to close as a result of the coronavirus lockdown. Despite this disruption, the project is progressing well and in the past year, the researchers have published their findings in three papers.
Magali and Ritu have continued to develop their understanding of PlexinB1’s role in prostate cancer spread. The process in which a cell divides to form new cells is a very complex process, and cells need to be able to complete this properly to renew themselves as older cells wear out. Magali and Ritu have shown that reducing the amount of PlexinB1 in a cell disrupted cell division, and caused the cell to die.
The research has also given more insight into how PlexinB1 might be one factor which plays a role in hormone therapy resistance. Their findings suggest that by helping to control the movement and activity of two proteins inside the cell, the androgen receptor and the glucocorticoid receptor, both of which are important for hormone therapy, PlexinB1 might be involved in teaching prostate cancer how to avoid being killed by hormone therapy drugs.
As part of this project, Magali and Ritu are collaborating with another group at Cardiff University. The team in Cardiff discovered that a single, very small change in PlexinB1 DNA in tumours can switch PlexinB1 from a protein that blocks prostate cancer spread to a protein that dramatically increases spread. They will develop further experiments to investigate the mechanisms behind this change and use that knowledge to develop potential new therapies.
As well as looking into how PlexinB1 behaves and how this influences prostate cancer, the team began to look at different ideas for treatments which target the protein. One way in which they are working on this is by developing antibody drugs which will attach directly through PlexinB1. They have been working on this for some time.
This year, they have also started creating shortened versions of PlexinB1 using splice switching oligonucleotides or SSOs, short sequences of DNA or RNA which can be used cut off the active part of the protein. This shortened PlexinB1 can then act as a decoy. Normally, proteins have to fit cells to activate them – a key fitting a lock and turning it to open the door. The decoy PlexinB1 fits into the cell but it doesn’t cause the cell to become activated – the key fits the lock but can’t turn it, and blocks other keys. This prevents other proteins from activating the cell and prevents the spread of prostate cancer. In the future, they hope to continue to develop SSOs as a potential new treatment for prostate cancer.
The project is now in its third year. This year, Magali and Ritu will begin looking into creating their own cutting edge 3D models of human prostate cancer from human prostate cancer tissue. These can then be used to explore PlexinB1’s role in prostate cancer and test new treatments, including the anti-PlexinB1 antibodies. They will then continue to study PlexinB1 to see if it can be used to predict how aggressive an individual’s prostate cancer is and how it may spread.
Read Magali and Ritu’s research papers here: