In our group a high risk subgroup of ALL was discovered which is called BCR-ABL-like ALL, so that probably needs a little bit of introduction into the BCR-ABL subtype. This is a well-known poor prognostic subtype that fuses two genes together, the BCR gene and the ABL gene, and this leads to activation of the ABL kinase in B-cells where it should not be active. That’s the cancer driving lesion in about 5% of children but a much larger proportion of adults with ALL. What we discovered is that there is a group of children that’s about the same size that looks like this group in gene expression patterns and poor outcome but they don’t have this specific BCR-ABL fusion gene in their genome. Another group in the US also discovered this and so step by step we’re getting closer to the identity of this group.

Now it appears that there are a lot of different fusion genes, different kinases that can be partnered with up to fifteen different partner genes, making this very heterogeneous group but probably with the same outcome which is activated tyrosine kinase signalling and then associated poor outcome.

Tyrosine kinase inhibitors are used currently for BCR-ABL positive ALL; in adults it has been used already for ten years and in children also with very good results. So where these patients were one of the poorest subgroups now they are with outcome among the other subgroups, so that’s been a big improvement. The next step is indeed to see whether these novel tyrosine kinase fusions will be sensitive in the same way to these inhibitors. We’re collecting with a lot of different groups in the world preclinical evidence to show the sensitivity and also there is early clinical data already, especially of course the step to treat different ABL fusions with imatinib or dasatinib which are the current inhibitors is not such a big step for a clinician. So refractory patients or relapsed patients for which there are no current treatment options are being treated and largely with success. So these novel fusion cases respond in the same way as the BCR-ABL fusion response.

Then there’s a separate class that is the JAK fusions, so that’s a different kinase and it responds to a different inhibitor. So these are the JAK inhibitors and here also preclinical data is solid to show that these are sensitive to an inhibitor such as ruxolitinib. But since this is not a standard drug in ALL treatment the step to early clinical studies is more limited but there is a similar improvement that could be made in the outcome of these patients.

Is ruxolitinib from the same class as trametinib?

Trametinib is another inhibitor because it’s a MEK inhibitor. So if tyrosine kinase activation happens quite close to the cell membrane, it’s a receptor or it’s a kinase that’s fairly close to the receptor, and starts downstream signalling there can be different paths. The MEK pathway is another path that could be activated so that makes it also more complicated because tumour cells can escape by activating one of the other routes. But the MEK inhibitors, currently the most obvious genetic aberration to link to them to sensitivity is RAS pathway mutations. So these signal directly downstream to MEK, ERK and then down to the nucleus where they start transcription. In our lab we’ve shown that in ex vivo patient cells, so we take patient cells and we do a short exposure to trametinib, that these cells die. This is important because many of the RAS mutated leukaemias are not sensitive to, for example, prednisolone which is the main drug in ALL treatment. So by giving them something extra hopefully that can improve their outcome. But these are really still at the preclinical stage so not yet in patients.

Could you tell me about any ongoing trials which are at the clinical stage?

The US is already starting a clinical trial where they will up front identify these novel tyrosine activating lesions in patients and then add imatinib or ruxolitinib, depending on ABL or JAK class aberration, to the induction treatment to see whether they respond and if they respond they can keep receiving the drug. So that’s one big clinical trial; it’s very important to see what’s going to come out.

There are other trials, there are, of course, many new drugs and if you mention MEK inhibitors there’s not only trametinib but there are many of these potential therapeutic agents that need to be tested. The way forward now, especially for relapsed children, the population is actually limited so you can’t test every drug you would like to test in clinical trials. The idea is to do these basket trials where patients will be pulled together based on their genetic aberration and not primarily on their type of tumour. So to increase patient numbers with each specific aberration and then to be able to test sensitivity to these different promising drugs. So in the Netherlands we have some trials going but we will also enrol patients in European trials simply to together have sufficient patients and power to help develop these new drugs.

What do you think we will see in the future regarding sequencing?

You can’t really look too far into the future but sequencing costs are going down and currently many tests are being done already together make up also for an expensive diagnostic process. So that’s one; second, the clinicians need to be convinced that detecting these aberrations will really help them to improve treatment, so that is clearly a case that you would need to detect them. I also think there will be more targeted solutions to diagnostics. These can be very simple like FISH, seeing a kinase is broken which now is done for BCR-ABL but could be done for the other kinases, followed by PCR. We can exclude the known subtypes so they will not have to go through this more expensive diagnostic pipeline. Targeted sequencing specifically for the lesions we know will cover already a large proportion of them so in that way we can balance cost and benefit for the patient. We can have both.