A novel drug target has been discovered by researchers at the Francis Crick Institute. The identification of this target is particularly exciting as it is unique to tumour cells, meaning that it is less toxic compared to existing therapies. Healthy, ‘normal’ cells remain unaffected upon administration of the drug.
In a press release, the first author of the paper, Laura Novellasdemunt, Researcher at the Francis Crick Institute, commented: “There has long been a need to find more effective and less toxic drugs to treat bowel cancer… we have found a novel drug target that could provide the basis for a better therapy in patients in the future."
Wnt signalling pathways are involved in a number of vital signal transduction pathways which span a multitude of different organs. Existing cancer drugs designed to block Wnt signalling are non-specific to tumour cells and therefore lead to significant adverse events, often observed in other parts of the body.
The wild type APC gene is a tumour suppressor, which offers protection from cancer by preventing abnormal cell growth. Mutations in the APC gene are known to cause bowel cancer, by promoting excess activity of the Wnt signalling pathway.
The researchers made several specific cuts in the APC gene using the gene editing tool CRISPR. This allowed them to identify the precise region of the gene responsible for the upregulation of Wnt signalling, which was ultimately responsible for the cancer formation. The research was published, October 17, in Cell Reports.
Utilising several molecular techniques, the researchers were able to identify a protein, known as USP7, exclusively involved in the over-activation of Wnt signalling in tumour cells. They then went on to prevent the protein’s activity in the mouse model (using genetic deletion techniques and suppressive drugs) which lead to a reduction in tumour growth. In addition, they observed no change in Wnt signalling in healthy cells.
"Current treatment for bowel cancer is mostly generic, while targeted therapy will help future development of personalised medicine," explained senior author, Vivian Li, Group Leader, The Francis Crick Institute.
The researchers are hopeful that the newly discovered protein will hold promise as a potential therapeutic target for the treatment of bowel cancer.
I spoke to Vivian Li, to learn more about her group’s research.
Do you think there is scope to explore the use of this protein as a drug target in cancers other than bowel cancer?
The protein we identified, USP7, is a potential drug target for cancers with APC mutations. APC mutations have been found not only in most bowel cancer but also in other cancer types such as liver cancer. So potentially USP7 can be explored as drug target in other cancers with APC mutations as well.
Could you tell me more about USP7? What drugs did you use to effectively block the protein’s activity?
USP7 is an enzyme that removes degradation signal from proteins, thus protecting specific protein from being destroyed. We found that USP7 protects a particular cancer-causing protein in cells, leading to its accumulation when the APC gene is mutated. Therefore, targeting USP7 can destroy the cancer-causing protein and suppress tumour growth.
Several compounds have been previously reported to target USP7 specifically. We tested a few commercially available USP7-specific drugs, and they all showed consistent suppressive effect.
What molecular techniques were used to identify the protein?
We used genome editing tools (CRISPR) to generate APC mutations, and used unbiased approach (mass spectrometry) to identify a protein (USP7) that binds to the mutant APC protein.
The press release mentions that there is intention to further investigate deletion of the USP7 gene and the effect this will have on the development of bowel cancer. Will this research be continued by your team specifically? Could you provide us with any further details about next steps?
Yes, there is follow-up research ongoing in the lab. We are now generating mouse models to test the tumour suppressive function of USP7 in animals. We want to further study if targeting USP7 can delay bowel cancer onset and/or reduce tumour aggressiveness.
Vivian Li, was speaking to Laura Mason, Editor for Technology Networks.