The idea
Led by Dr Srinivasan Madhusudan at the University of Nottingham, this research project looked at how to improve the effectiveness of chemotherapy by including other drugs that make the cancer cells more susceptible to damage done by the chemotherapy.
Project background
With very few treatment options for ovarian cancer, when women become resistant to one of the two key drugs used in chemotherapy, there are few alternatives. Currently, a significant proportion of women will eventually develop resistance to platinum-based drugs. Overcoming this resistance to chemotherapy is a major challenge and a key priority in Target Ovarian Cancer’s research strategy.
This research project looked at how to improve the effectiveness of chemotherapy by including other drugs that make the cancer cells more susceptible to damage done by the chemotherapy. While platinum treatment damages the DNA in tumour cells, making them less stable, some tumours are able to develop resistance to this treatment by increasing their ability to repair the damaged DNA.
Research results
The research team developed a strong collaboration with a group of chemists from the prestigious National Institute of Health (NIH) in the United States. This gave them increased access to a large library of chemicals and research expertise.
Results from this project showed that a protein called ‘flap structure specific endonuclease’ (FEN1), which has an important role in DNA repair, is present in ovarian cancer cells at levels that are higher than normal. Furthermore, survival was worse in patients who had tumours with high levels of FEN1.
In the laboratory, blocking FEN1 with a drug increased the sensitivity of the ovarian cancer cells to platinum. Cancer cells that were deficient in BRCA2 and POLβ (both involved in DNA repair) were also sensitive to treatment with the drug targeting FEN1 (this process is called synthetic lethality, which is how PARP inhibitors work). Together, the results provide evidence that FEN1 is a promising anti-cancer target in ovarian cancer.
Why is this research important to those affected by ovarian cancer?
These results are the first evidence that targeting FEN1 could be a new strategy for treating ovarian cancer. If successful, these drugs could be tested on women in a clinical trial to see if they could be a potential new treatment for use alongside chemotherapy to overcome resistance.
Fact file
Researcher: Dr Srinivasan Madhusudan
Institution: University of Nottingham
Project dates: October 2015 to June 2016
Funding awarded: £129,045
Project status: complete
Key publications: Mesquita KA, Ali R, Doherty R, Toss MS, Miligy I, Alblihy A et al, FEN1 blockade for platinum chemo-sensitization and synthetic lethality in epithelial ovarian cancers; Cancers, 2021 13(8): 1866. https://doi.org/10.3390/cancers13081866
