Basically what I’ve been working on mostly is a specific subtype of acute myeloid leukaemia, the so-called FLT3 mutated leukaemias. FLT3 is a very recurrent mutation in acute myeloid leukaemia and it’s unfortunately one associated with a poor prognosis for patients. So acute myeloid leukaemia unfortunately it is itself a very aggressive disease and the outcome, generally speaking, for patients is still not satisfactory. But FLT3 mutated AML are a particularly bad prognostic group. We do now have some novel therapies [?? 0:38] for leukaemia. We have specific inhibitors that target this abnormal protein, this FLT3 protein, which is a receptor tyrosine kinase which can be inhibited by small molecules. But I have to say, and I think it’s commonly agreed in the community, that despite the fact that we’ve known about this mutation for a long time the reality is that these targeted therapies are not as effectively clinically as we would have hoped. This raises the question as to why this happens and is there any resistance mechanism, is there anything that we can do to try to understand why these therapies have not fulfilled their promise to a certain extent?

My personal interest then has been looking at what happens to the metabolic rewiring within the cells when they are treated with this inhibitor for FLT3. So I’ve done some preliminary work where I’ve basically looked at what happens to the metabolism of FLT3 cells before they get treated with the specific inhibitor and then I went on to look at what happens once we inhibit the FLT3 protein with this specific molecule and see whether there are changes in the metabolism which cells use to adapt to the therapy and somehow overcome the deleterious effect that the therapy should have, so establishing a resistance mechanism effectively. By looking at the changes in the metabolism then we could potentially identify other therapeutic vulnerabilities which we can use in combination with the FLT3 therapy in order to improve our ability to eradicate these cells.

Effectively what I have been able to show so far has been that FLT3 cells use a lot of glucose, sugar effectively, to fuel their metabolism but this process is impaired, is reduced, once they are treated with the FLT3 inhibitor and at that point their metabolism switches and starts to utilise more other nutrients, glutamine, which is one of the most abundant amino acids in our body and one of those that we can easily find to our nutrients as well. As a result of that glutamine metabolism becomes a potential therapeutic vulnerability when it’s targeted in combination with FLT3 inhibition.

Luckily we now have new and interesting cancer metabolism and over the last at least five to ten years there has been an enormous amount of information gathered about the role of metabolism in cancer. Luckily there has been also development of new novel small molecule inhibitors of metabolic pathways. We do have inhibitors of glutamine metabolism available with us and that means that we can actually use them in combination with FLT3 inhibitors and that’s exactly what I did in my preclinical work which I presented yesterday is to show that when you combine a FLT3 inhibitor with a glutamine metabolism inhibitor the combination of two is able to synergise and kill the leukaemic cells more effectively. It is obviously at the moment a preclinical information and I’m still trying to work out exactly the whole mechanism behind that because obviously what glutamine does in order to support cell survival is still not entirely clear. I have shown some possible explanation for that, about the role of glutamine in redox metabolism within the cells, about the role of glutamine in supporting the respiratory function of the cells. But above all the most important thing for us is to try to validate this in different models, so using both human cells lines, using primary samples from patients and animal models in order to have significant preclinical evidence that this combination treatment might be actually beneficial for patients. Once we have gathered all this information, and I am hoping to be able to do so in the next few months and potentially within a few years be able to, me and other people who are working on this, publish and demonstrate this is actually possible. Then the next step will be to take this on to the patients obviously.