Drugging “undruggable” transcription factor drivers in cancer
Dr John Bushweller - Unviersity of Virgina, Virginia, USA
Transcription factors are a class of targets with a lot of potential for cancer therapy because we can change the whole gene expression programme of the cell but they’ve traditionally been viewed with a lot of scepticism by pharma for many good reasons. But there’s emerging successful efforts that are demonstrating that, while challenging, they are druggable and the effects can be quite profound so we’re excited about that possibility.
How are they approached as a novel target?
I was asked that question when I spoke this morning and there’s a couple of things I think you have to keep in mind. One is the design of the assay - when you’re looking for molecules that will modulate this function how you design the assay is really important so that you get things that do what you want. Secondly is the selection of chemical space to look in. Over the years we’ve tried a lot of different approaches and, as I said, a number of people have had more luck with fragment based approaches recently, that seems to be giving us more positive hits and a better path forward. The transcription factors, the kinds of targets you’re looking at are either protein-protein interactions or protein-nucleic acid interactions. The way you choose to look at those or the portions of the protein that you use can affect the outcome and what you’ll get, whether that compound will be active in a cell or not where there’s a more complex milieu and they’re more usually in the context of some multi-protein complex. So all those things are really important when you’re thinking about targeting this class of protein.
What results have you found?
Yes, we described last year a small molecule inhibitor of a transcription factor fusion that arises in about 10% of acute myeloid leukaemia patients. This was able to restore the normal, or more or less normal, gene expression programme of the cell when we treated with that so that was very exciting. We also were able to show efficacy in a mouse model and against human patient material. So all that was nice validation of the approach that we’re taking. Now efforts are focussed on trying to commercialise that agent to get it into the clinic ultimately.
Are there any limitations to the ways you’re approaching these therapies?
None other than the things we run into typically in any drug design effort. You worry a little bit about you’re altering a large swathe of genes when you alter one of these transcription factor behaviours. So what the impact of that will be in other cell types or in tissues is something we have to see, we have to see what happens with these.
Have any adverse effects been reported?
For the inhibitor I described to you we have not seen any toxicity. It’s very specific for the fusion protein in that leukaemia and we’ve shown that it doesn’t affect the wild-type form of the protein which is also present. So in that setting, at least with this inhibitor, we have a very specific effect and we haven’t seen any evidence of toxicity in any major organ or in the hematopoietic compartment.hematopoietic compartment.
What about mutations?
Two comments: one, I think, and there’s evidence for this, that the transcription factor alterations that are occurring in many cancers, not all but many, are drivers of the enhanced mutagenesis that’s going on in these cells. So, perhaps, if we can shift that gene expression programme back you can limit the amount to which the cell could evolve to try to get out from under things, that’s my hope. In terms of any kind of targeted therapy, cancer cells have proved amazingly resilient in finding ways around these targeted agents so that’s something we always need to be thinking ahead, how do we get ahead of that process, because it almost certainly will occur.
What about combination?
There are now lots of mouse models where an alteration of a transcription factor is combined with an activated kinase of some kind. Those models recapitulate what we see in patients actually amazingly well. So there’s clearly a need in these cancers for hits on transcription factors which block differentiation and also on various kinds of kinase signalling which usually drives proliferation. So the idea that we have many drugs that can hit the kinase signalling component of that but now if we can add hitting the transcription factor component, that really has a lot of potential combinatorially.