Identifying drivers of resistance in childhood brain tumours

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Published: 11 May 2018
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Dr Pratiti Bandopadhayay - Dana-Farber Cancer Institute, Boston, USA

Dr Bandopadhayay speaks with ecancer at the Cancer Research UK Brain Tumour Conference 2018 in London about resistance mechanisms in paediatric brain tumours.

Taking cues from treatment resistance in melanoma, she describes how BRAF targeted therapies may be subverted by genetic rearrangement, and the prospects of immunotherapies in childhood patients.

Brain tumours are the leading cause of death of kids from cancer. So a few years ago it used to be leukaemia, brain tumours are now the number one cause. Unlike the other cancers we haven’t really made great outcomes or huge changes in our outcomes and for those that survive they have a lot of side effects. So the current treatments of surgery, chemotherapy and radiation really aren’t enough.

What’s happened scientifically over the last decade is we have now sequenced the human genome, which has been a phenomenal achievement, which means we can now sequence the genomes of human cancers and particularly brain tumours. This is an area that we are exponentially learning, we are rewriting the textbooks in real time and we have, for the first time, learned about all the mutations that are occurring in many of these tumours. Some of these mutations have drugs that we can use to target them.

The challenge that we have is how do we translate all of this into clinical practice at a rapid speed to help the kids that are being diagnosed at the moment.

How is that achieved?

It’s a good question. Collaboration is really important, so meetings like this are key to bringing the field together from all over the world. There are a lot of different platforms now that different groups have designed to look for the mutations that are being tested in different parts of the world. We need to work out the best way to look for these mutations; we have to work with drug companies to get drugs developed for kids and get them into clinical trials quickly and we have to design drugs that will actually get into the brain. A lot of drugs are actually designed not to get into the brain so that’s not very helpful for kids with brain tumours. Then we’ve learned from adult cancers that tumours will become resistant to drugs so we have to practically study resistance mechanisms so that we can have combination treatments.

How do these resistance mechanisms work?

One of the areas that it’s the most actually tested in is adult cancers, for example melanoma or lung cancers. Melanoma is often defined by mutation in a gene called BRAF which actually is also found in paediatric brain tumours. So the drugs that have been used for adult cancers are now actually in clinical trials for the BRAF inhibitors. In melanoma what the adult doctors have found is that when you inhibit that protein of BRAF other proteins can actually turn on to take over the function or you can actually get mutations that stop that drug working. So that’s a possibility that we’ll see in the paediatric cancers. We have found studying other inhibitors in other brain tumours in the lab that the cancer cells will find other ways of turning on genes, if not through mutation sometimes by actually changing the chromatin or the regulatory structures as well. So there are multiple ways they can become resistant.

Is immunotherapy being tested in brain cancer?

Immunotherapy has been very exciting, that’s been the real excitement in oncology over the last few years. There are definitely attempts to try and translate this into kids with brain tumours and adults as well. Inflammation, which is what is induced by these drugs, can sometimes not be great for the brain because you can imagine you have the brain and then there’s the skull around that and if you get a lot of swelling then that could actually cause some compression. So the challenge in brain tumours is how to do that in a way that’s safe for the kids. But there’s some really exciting work going on along those lines across the world.

What are the key messages?

It’s an exciting time. I come from Dana Farber and Dana Farber is named after Sidney Farber who in the sixties showed for the first time that you could make leukaemia go into remission. Here we are fifty years later curing a lot of kids so I think this is the time for brain tumours. I see a lot of hope. We have learned so much biology in the last few years. In paediatrics we work together which is a really, really important thing. So our messages are that we need to keep working together, both in academia but also with industry, with the drug companies and also with the foundations that are raising a lot of the funds, like Cancer Research UK. It’s going to take a team but actually I’m really excited that we are going to get there.