Personalised approaches to paediatric ependymoma

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Published: 11 May 2018
Views: 1393
Dr Stephen Mack - Baylor College of Medicine, Houston, USA

Dr Mack speaks with ecancer at the Cancer Research UK Brain Tumour Conference 2018 in London about the genomic and structural biology of childhood brain tumours.

He describes how new epigenetic insights are opening treatments for patients beyond radiotherapy, and anticipates how mouse models may lead to clinical trials.

I was talking about some of the challenges we’ve had and we’ve been focussed on the paediatric brain tumour. The field has really exploded in terms of sequencing technology, specifically in cancer, and our ability to identify genes that are involved in the disease process with the motivation that we can pair these with drugs. Those are ongoing efforts right now in clinical trials, personalised medicine approaches.

We applied this to a paediatric brain tumour type called ependymoma. I’ll take a step back first and acknowledge that we were finding that what is distinct in paediatric brain tumours is that they have a much lower mutational rate than adult tumours which makes it challenging to identify targets for therapy. This is one case in a tumour called ependymoma, it happens in young infants. It’s a highly lethal brain tumour, the treatment is surgery and radiation and then when these tumours recur, which they often do in infants, we re-irradiate and we re-irradiate and so you can image the long-term neurological side effects of that. So we have no target or drug that we can recommend for these patients at the moment.
So we thought that genome sequencing would be our answer to that, that we’d identify the hits and then these would pair us with a pathway and a drug and we’d be able to test something in clinical trials for patients. We were disappointed, though, in that it didn’t fit the textbook approach for many adult cancers. It was clear to us that we needed to utilise more different approaches, looking less at the sequence of the DNA but more about how the DNA folds and what regulates the genes that are transcribed from the DNA. It is really advancements in genomic technologies that have allowed us to perform this, the field is called epigenetics or transcriptional regulation, where we’re looking at the proteins that regulate how high a gene is expressed and the folding of chromatin. This really mapping across the genome has given us a new paradigm because this has allowed us to identify pathways that we never would have thought of using more traditional approaches. We showed at least a proof of principle that we can pair this with specific drug targeting strategies.
So we think that this is a new paradigm that is complementary with more traditional approaches which could be effective in many paediatric cancers that have very low mutational rates or even adult cancers where we have found the actual driver event that we know causes the disease but we’ve yet to identify a drug that we can pair with it.

What are the limitations?

One of the limitations, at least in our system, is the models. We’re learning about the disease faster than we ever have. One of the major challenges is trying to develop animal models that we can test. So we identified a drug and we tested it in one animal model and we’d like to expand that to more mouse models to be able to have solid evidence that this might be an effective target that we can bring into clinical trials. We’ve identified a lot of targets and just coming down to our most promising one and then validating that in mice would be the evidence we need to take that to clinical trials. Because, at least in North America right now, there are no agents that we can recommend for clinical trials for these patients so they are waiting for something that we can provide them.

The key message is, in terms of this field, that even though it has been challenging to identify molecular targets, times are rapidly changing in terms of our understanding of the epigenetic basis of these specific tumours. We’re building models as well so in this particular paediatric brain tumour type, and it could be more generalised in terms of all paediatric brain tumour types, that we’re developing both new approaches to understand the disease and models. Pairing those together will allow us to develop new therapies that we can advance pretty rapidly into clinical trials. So even though for some tumour types that may not have agents available our understanding of the disease is rapidly progressing for us to be able to develop those.