Leiden researchers receive over €1 million for research into BRCA1 cancer treatment
Women with an inherited BRCA1 mutation have an increased risk of breast and ovarian cancer. This type of tumour depends on the protein EXO1 to survive. Thanks to a KWF grant, Sebastian Pomplun, together with geneticist Sylvie Noordermeer, is investigating new inhibitors to disable this protein.
The team hopes to identify a new treatment strategy for tumours that no longer respond to existing therapies. Each year, more than 15,000 women in the Netherlands are diagnosed with breast cancer and around 1,400 with ovarian cancer. Between 5 and 10 per cent of breast cancer patients carry an inherited BRCA1 or BRCA2 mutation, which substantially increases the risk of developing cancer.
Circumvent resistance
Targeted treatments, such as PARP inhibitors, already exist for patients with a BRCA1 mutation. These drugs impair cancer cells’ ability to repair damaged DNA, which can slow tumour growth. Over time, however, cancer cells can become resistant, allowing the disease to return. ‘There’s an urgent need for new strategies that circumvent these resistance mechanisms’, says Pomplun.
The tumour’s Achilles heel
Pomplun and Noordermeer’s research focuses on a potential Achilles heel of BRCA1-deficient tumours: the protein EXO1. Previous work by his team has shwon that these cancer cells are highly dependent on EXO1 to repair their DNA and survive.
‘By specifically inhibiting EXO1, we hope to damage the tumour cells so severely that they can no longer maintain their genome and die off, while leaving healthy cells far less affected’, says Pomplun.
The research is particularly relevant for patients with BRCA1-related cancer for whom existing treatments have stopped working. As EXO1 acts through a different biological mechanism from current drugs, this research could ultimately lead to a new treatment option.
New drug molecules
The team will use the €1.18 million grant to search for potent drug molecules that bind specifically to EXO1 and block its activity. Using computational modelling and chemical synthesis, the researchers will develop a range of candidate inhibitors that will be tested in the laboratory for efficacy and selectivity.
The most promising inhibitors will then be tested in preclinical models to determine whether they can suppress the growth of BRCA1-deficient tumours. In a later phase, the best candidate inhibitors will be tested in a select group of patients through the Oncode Patient Involvement programme.
Pomplun is delighted that this grant will make the research possible. ‘I’m thrilled that Sylvie Noordermeer and I have been awarded the grant to target EXO1. It’s a tricky target, but it’s the kind of target that offers huge potential for highly selective, well-tolerated cancer treatments. We’re ready to bring our A-game over the next few years alongside our collaborators, Prof. Perrakis and Prof. Jonkers, to crack this nut.’
Towards a new treatment
The research marks the first step in a longer drug development pathway. If the inhibitors prove effective and sufficiently safe in preclinical studies, further research will be needed to develop the molecules and ultimately test them in clinical trials with patients.