Personalised therapy in ovarian cancer: targeting flap structure specific endonuclease (FEN1)

Led by Dr Srinivasan Madhusudan, 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.

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. 

Led by Dr Srinivasan Madhusudan at the University of Nottingham, 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.  

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. 

Results from this project were published in the journal Cancers in April 2021.