Childhood Cancer 2016

ALK mutations in paediatric tumours

Dr Suzanne Turner - Cambridge University, Cambridge, UK

Research in my lab focuses on a protein called anaplastic lymphoma kinase or ALK and this is a protein which was discovered back in 1984 to be switched on in a form of childhood cancer called anaplastic large cell lymphoma, ALCL. Basically, the protein gets switched on at a time in development when it shouldn’t be active, so normally ALK is only active in the nervous system during development in utero. What happens in cancer is it becomes switched on by a number of different mechanisms in the tumour cells. ALK is a protein which we call a kinase and kinases are quite important proteins in the body because they’re very fundamental to instructing the cell how to behave and what to do. So when they get aberrantly switched on they start to tell cells to do things they shouldn’t be doing like dividing and proliferating rapidly.

Now the nice thing about kinases is that they need energy to function and the energy they need comes in the form of a molecule called ATP. ATP sits into a little pocket within the kinase protein and that gives us a really nice place to start when designing drugs because if our protein is very much driving the tumour growth, which is the case with ALK, then we can design drugs which sit in that energy binding pocket and prevent energy from getting in and therefore cause the protein to stop working. What happens then is the tumour cells also stop working and they die and that’s the basis of targeted therapy which has been around for a few years now mostly targeting kinases like ALK. But targeting ALK specifically has always been a bit of a problem because largely it was only known as being activated in a small proportion of children with cancer which unfortunately didn’t spark the interest of a lot of pharmaceutical companies who weren’t interested in childhood cancers, particularly when I started working on the proteins some fifteen years ago. In that time ALK has been found as expressed in a number of different cancers, most notably in lung cancer in adults and of course this has now sparked a lot of interest in this as a drug target.

So in the last five to ten years a number of ALK inhibitors have been developed, the main one is a drug called crizotinib which has been very successful, it’s been approved for use for adults with lung cancer. It’s also now under trial for children with ALK related cancers, so for children we’re talking about neuroblastoma, which is a cancer of the peripheral nervous system, and anaplastic large cell lymphoma, which is a lymphoma, it’s a cancer of our immune system. So children who have these ALK expressing tumours and some other, rarer, tumours are eligible for use of crizotinib when their tumours express ALK.

So this raises an interesting concept that we now have a drug that targets ALK that we can now use through clinical trial in children with ALK expressing cancers. But what we know that what happens with adults with ALK expressing tumours that get ALK inhibitors is that inevitably in some of the patients their tumours become resistant to these inhibitors. That happens by two mechanisms: the first is that either ALK is massively over-expressed in the tumour so therefore you need more drug to target it and so the tumours in that way bypass the inhibitor. The other way they do this is they mutate that energy binding pocket so that the drug can’t fit in any more but energy can and then again they become resistant to the drug. There’s a third route and that is whereby the cancer cells are quite smart, they evolve much like bacteria evolve resistance to antibiotics, but they evolve in such a way that they develop bypass tracks, pathways which take them by ALK, the kinase, so they don’t need it anymore and then they become again resistant to the drug.

So this is where I get to the grant that is funded by Children with Cancer UK for work in our lab where we want to pre-empt what’s going to happen in the tumour cells when children are treated with ALK inhibitors. We want to find out what are those bypass tracks that will be activated potentially in the tumour cells that we can then think proactively about how we might then target children with relapsed disease that aren’t responding to ALK inhibitors.

The funding with the charity is enabling us to do a screen, essentially, through a neuroblastoma, we’re also working on the lymphoma as well in the lab, and to try and find what those bypass mechanisms might be.

What is the anticipated impact on children with cancer?

Once we’ve identified what these bypass mechanisms are, what these tracks are that are being used by cancer cells to evade ALK, so to become independent of ALK and ALK inhibitors, we can then design therapies that would be specific to those bypass tracks. This may be some way off in the future, as I said, children are only just now being treated with the ALK inhibitors, with crizotinib under clinical trials mostly, and therefore we don’t expect a resistance to develop in these children for a few years yet, we hope. But in the event that they do, and we expect that they will develop resistance based on what we’ve seen with adult patients treated with crizotinib for ALK expressing lung cancer, we will be in a better position to know which pathways to look for in these children’s tumours and therefore to design therapies which then target those bypass mechanisms.

So it’s really a way of pre-empting what the tumours cells will do, how they’ll respond to these ALK inhibitors and therefore how we would be able to treat children if in the event they come back to the clinic with ALK resistance relapsed disease.