We work on the breast and ovarian cancer predisposition protein BRCA1; that’s the one that Angelina Jolie has a mutation in the gene for. And we are trying to work out what it does, how it prevents cells becoming tumours. We are very interested in understanding in particular its conserved N-terminal piece which is important as an E3 ubiquitin ligase and we now know that it regulates the way that DNA is wrapped up and in particular the ways that wrapping prevents cells from repairing their DNA. And actually what BRCA1 does, we think, is move some of that wrapping out of the way so that the DNA can be accessed and repaired properly. There are implications for treatment because it turns out that, that process is important, for example, for olaparib response. It’s also important because it turns out that the way this thing functions is not important for a number of other ways that BRCA1 works. That’s actually quite interesting because we know that resistance to PARP inhibitors occurs through a certain pathway but because the protein, this portion of the protein isn’t required for other functions any resistance to those other functions will be through a different pathway so there is more than one way of hitting a cell that doesn’t have BRCA1, ligase dependant and ligase independent. So, I think it is quite useful from that perspective.
Can you explain more about this hidden target?
Imagine you are treating somebody with no BRCA1 or low BRCA1 levels and they are becoming resistant to PARP inhibitors. This tells you there are other mechanisms that have totally different resistance mechanisms, so if you are to hit them with something else like a replication blocking drug it wouldn’t be resistant, wouldn’t become resistant in the same way that they become resistant to the PARP inhibitors. So the cell would have to develop different mechanisms of resistance so the chances of being able to kill the thing are much higher if you can hit the different pathways.
Have there been any new combinations?
Yes, there’s just been a trial of carboplatin and olaparib which fits into this way of thinking and does seem to work rather well, which would seem to fit very well with the biology.
Did you provoke any interesting discussion with your talk?
Somebody said could you use this understanding in genome editing, which is not something I’d thought of before. That was from Adele and was a very good question. I think maybe you could actually because what we’ve found is the way that BRCA1 controls resection lengths and of course that means we can manipulation resection lengths which might be really helpful for improving targeting in CRISPR editing but that’s just an idea. I haven’t tested it yet and it might not work, but it’s a nice idea.
