Novel drug targets and potential combinations in childhood brain tumours

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Published: 26 Jun 2014
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Dr Stefan Pfister - German Cancer Research Center (DKFZ), Heidelberg, Germany

Dr Pfister talks to ecancertv at WIN 2014 about novel drug targets and potential combinations in treating childhood brain tumours.

Overall, of course, it’s a rare entity, as all paediatric tumours. So basically all paediatric tumours together are about 1% of all cancers but amongst the paediatric tumours the brain tumours nowadays are the leading cause of mortality, or patient death, and this is why we are so much interested in improving their situation.

Can you tell us about INFORM (INdividualised Therapy FOr Relapsed Malignancies in Childhood and Adolescence)?

After the primary therapy that we give to all patients, usually in nationwide or European protocols, we nowadays can cure about 75% of patients but whoever relapses, however, usually has a very poor survival. So we decided that we have to do something for this group of patients independent of the tumour entity that they are suffering from and we try to foster a re-biopsy at the time of relapse to really then do genomic analysis on the re-biopsy and the relapse to be sure that we are actually facing the biology that is present at that time rather than taking the biopsy from the primary tumour. Then we try to infer targeted therapies from this molecular work-up that we are doing for the relapsed situation because we think, or we hope, that this will be better than just giving a standard oral chemotherapy.

How does INFORM work in practice?

As you can imagine, these children are treated in more than fifty different places in Germany and about twelve different study centres are involved in that so it was kind of challenging to get all of them together but I think that we are all unified by the wish of better helping these patients. We’ve set up an infrastructure now where in all of these fifty places tumour tissue can be frozen down and submitted to a central laboratory which is in Heidelberg and we try to turn around these samples within four weeks between the biopsy and delivering the data to the treating physician. We try to provide rational drug targets; at the moment it’s at the discretion of the clinician, the local clinician, to take them further for an individual therapy and in the future, once this concept is better established and all the infrastructure is working really on a daily basis, then we want to really run a clinical trial where we compare the principle of individualised therapy versus just giving a backbone chemotherapy as we do now.

What have been the results from the pilot phase?

So far we have, and this is encouraging, we have done about thirty pilot patients because the registry study, as such, is not open at the moment, we just started to establish the infrastructure. Amongst these thirty cases we have identified or been able to identify drug targets in more than half of the cases which we think is quite good. Now it will of course be interesting on getting the feedback from the clinicians. We already know that we had some very favourable responses but we cannot really talk about frequencies and durable responses yet because we just started last December.

Are the safety concerns of using targeted treatments in children different to those in adults?

We even have more limitations to get access to drugs, of course, because usually you have to have completed an adult phase I study before you can start a paediatric phase I and usually there is not a lot of interest with the pharma companies to do that at all because this will never be a big market. But, on the other hand, we try to find different ways on getting access to drugs and one of the most convincing arguments from a paediatric oncology perspective is that usually the genomes of children’s tumours are relatively simple so you’re very close to the actual driver mutation and this is also an attractive option for a pharma company to really give a drug where the target is actually present and there is not a hundred other potential targets which probably could mask the effect of this drug. So we hope that with this argument we will convince more and more companies to be interested in that.

Can identifying targets in children inform our understanding of adult tumours?

As I said, the genomes are simpler so it will be much easier to interpret the results of giving a targeted drug, even a monotherapy, and probably the mechanisms of resistance because it’s just less noisy and less, what we call, passenger mutations.

Where next for your research?

Of course inferring targets and drugs from the genome sequencing data is a very far distance to bridge. In principle you should have a functional genomics approach for every patient in between, where you would do some kind of in vitro or in vivo drug testing to really show that this is working. So this is something where we are currently trying to really fill the gap and for the most interesting and common targets we also try to really do some more in vitro and in vivo work prior to giving it to large cohorts of patients.

Anything else you would like to add?

One thing that I also mentioned in my talk was that, especially in this kind of relatively simple paediatric tumours, we often have cases also where we haven’t identified a clear driver mutation at this stage even and we think that, and we have good evidence now that, if you integrate epigenomics information rather than only looking at the pure mutations in genes that we will be able to really fill these gaps of cases where we don’t find an obvious driver. This is something that will probably also be interesting for adult oncology because this is something that is probably not a mechanism that is restricted to paediatric tumours.