Professor Iain J McEwan, Dr Irene Hunter and Dr Craig Jamieson lead our ‘Hormone Therapy: Old Dog, New Tricks’ project which focuses on new approaches to hormone therapy to keep it working for longer. The team recently completed the first year of their three-year PCR project and you can read about this year’s exciting findings below.
Hormone therapy
Hormone therapy is one of the main forms of prostate cancer treatment but unfortunately it will eventually stop working for many patients. Hormone therapy works by stopping the androgen receptor from telling cancer cells to grow. The outside of the androgen receptor acts as a switch which is turned on by male hormones and turned off by hormone therapy. When this switch is on, the androgen receptor sends messages telling the cancer to grow. Sometimes different versions of the androgen receptor are made, called androgen receptor variants (ARVs). ARVs don’t have a switch so they are always turned on and hormone therapy is unable to turn them off.
There are currently no treatments that can overcome this resistance which makes it an important target for research.
What we know so far
Professor Iain J. McEwan, Dr Irene Hunter and Dr Craig Jamieson are exploring whether they can keep hormone therapy working for longer by targeting small drugs to a different, but equally important, part of the androgen receptor. This means that treatments will still work on variants that are missing the ‘switch’ that usually attaches to male hormones.
The team have already identified potential small drugs which could be used to stop the androgen receptor sending the messages telling the cell to grow. Alongside this, they plan to work with Elasmogen, a biotech company in Aberdeen, to develop new protein drugs called SoloMERs. The SoloMERs can be used in combination with the small drugs to lock the androgen receptor into place so that the small drugs have a better chance of working even more effectively.
Covid-19 has had a huge impact on labs across the country as many were forced to close in March last year due to the lockdown. Despite this disruption, Iain, Irene and Craig have made good progress on the project in their first year.
One of the original drugs previously identified by Iain and his team as having the potential to switch off the androgen receptor was CR097. To begin with, they tested CR097 and confirmed that it was able to switch off the androgen receptor. They then focused on developing and testing a number of small drugs based on CR097. These drugs were very similar to CR097 but with slight chemical changes.
They measured how well each of these drugs were able to stop androgen receptor function at different concentrations and in different prostate cancer cell models. This, and the slight chemical changes they had made, allowed them to look at which features enable the drugs to work best. They can now use the information gathered to create more drugs with improved effectiveness against the androgen receptor. For example, previous studies had shown that CR097 was broken down by the metabolism too quickly leaving little time for it to have an effect on the androgen receptor. Iain and the team found that making one very small chemical change could increase the time taken for the drug to be broken down.
In order to investigate how CR097 works, the researchers looked at what happens to three well-known genes controlled by the androgen receptor when the drug is applied. Their experiments showed that it was able to block the expression of these genes. They are continuing to look at the impact of CR097 on androgen receptor controlled genes and hope to be able to use their results to build a genetic profile of the drug.
The team also looked at whether CR097 could be used to tackle mutations in the androgen receptor protein that reduce the efficacy of hormone therapy. These mutations are known to convert drugs that switch off the androgen receptor to drugs that switch it on. They showed that CR097 was effective against a number of these mutations.
In addition to CR097, Iain and the team previously identified another promising small drug, CR369. They determined that CR369 is also able to switch off the androgen receptor and have now developed a series of small drugs based on this compound. The team have begun to test these small drugs in the same way as the series based on CR097.
The project is now in its second year. This year, Iain, Irene and Craig will continue to develop and test the small drugs based on CR369 to identify potential lead candidates. The team will also continue to investigate how both CR097 and CR369 work to switch off the androgen receptor. Finally, they hope to work with Elasmogen to begin generating the new protein drugs called SoloMERs and look at testing these in prostate cancer models.