NCRI Cancer Conference 2010, 7 November 2010, Liverpool
Professor Mariann Bienz – MRC Laboratory of Molecular Biology, Cambridge, UK
Signalling pathways as a target for cancer therapies
The main point really is that many of these important cancer pathways have been discovered in model systems, in particular in flies, and I started introducing, actually, the session with an old slide that I used to show some twelve years ago where there was the Wnt, the BNP TGF-β signalling, the knot signalling pathway and the hedgehog signalling pathway. They were all discovered in flies, in development obviously, and then they subsequently turned out to be, like I said, major cancer pathways. And more recently, it is actually more interesting than that, they all cropped up in stem cell compartments; so in the mouse people worked out they are required for stem cell activity, for stem cell function and now more recently more for cancer stem cell function. So they really are going to be really important to target in cancer.
How can we target these pathways?
One of the talks in the sessions showed actually that the Wnt pathway is required not just for cancer growth, which is what one wants to target, but actually for metastasis, for colonisation and micro-colonisation in a metastasis, and that is obviously the event that is important, that does kill people. So I guess that wasn’t really appreciated and that is only beginning just to come out, that it is not just the development of a tumour that a pathway like Wnt signalling pathway is initiated; we know that for colorectal cancer, but that its dissemination or micro colonisation of the target tissue in the metastasis also still requires that cancer, presumably cancer stem cells, and that pathway that makes it one, i.e. in this case the Wnt pathway. So it is turning out really interesting, actually.
Are there any drugs in development to target these pathways?
Well that’s the main problem, actually, and Wnt pathway is just about the worst of all of them because there are no enzymes to target but that’s true for notch and hedgehog and so on. Basically nothing is an easy target but they certainly aren’t easy to target, and in Wnt signalling the worst thing is that the pathway is activated at the level of beta catenin which is low down in the pathway, and that means you basically have protein/protein interactions to disrupt and that’s just a non-starter, that’s a red flag; that’s a non-starter certainly in former industry, they won’t touch that. So we have tried to do it and other labs in the field are trying to do it because it’s an opportunity for the academic labs to do this sort of high risk stuff. And we do it and then we hope we will learn something about the pathway itself and we will discover something, even if it doesn’t lead to a drug. And it’s going to work in the long run actually, it will be possible, it is just going to take a long time.
What progress has been made developing therapies to target these pathways?
In my session a postdoc of mine was able to talk because what I really hoped was to invite Fred de Sauvage from Genentech who has this hedgehog smoothened inhibitor and he published this a year ago. It was great stuff, so that’s I think the sort of dream come true that someone managed to target this development, important cancer pathway, with a small molecule. But he couldn’t come, so my own postdoc was able to talk about his work where we discovered some eight years ago that this new complex, which is required for beta catenin activity in flies, absolutely essential. In human cancer cells it contributes, so it is clearly in the same pathways conserved. It’s still unclear how important it is in, say, intestinal tumorigenesis, we will see, we are working on this, there is quite a lot of activity. Anyway, we decided, because this new one that BCL9 interacts with beta catenin in a different place. The trouble beta catenin is such a poor target is it uses its central domain to interact with all the different ligands including negative regulate, it’s like an APC annexin. So you really can’t disrupt that because you will disrupt negative and positive interactions, but this new one, BCL9, interacts north of that in the end terminus so it has its own dedicated surface. And that’s been really nicely shown structurally by others, not by us, so we thought why don’t we try to disrupt that because we can form the complex, and so on. So my postdoc actually found this natural inhibitor, natural compound, that was able to disrupt that interface but not the TCF, not the other interfaces, which does seem to work. But, to cut a long a story short, that’s what we probed for in vitro but what we actually seem to have got is something that destabilises beta catenin in vivo, so it just gets degraded. And the reason it probably does that is because it’s got this intrinsically unstable helix in the end terminus and that’s what this compound seems to make even worse, so it then aggregates and that’s recognised by the proteasome and it gets destroyed. So in other words we discovered, fortuitously, that probably one way of doing it is to decrease the stability of beta catenin, that might be a way to go forward, so having gone through it once we might do it differently the second time around, just as an example.
