Childhood Cancer 2016

miRNA screening for germ cell tumours

Dr Matthew Murray - University of Cambridge, Cambridge, UK

What we looked at a number of years ago was undertaking microRNA profiles in malignant germ cell tumours, so a relatively rare tumour that actually affects infants and children but also a tumour that goes into adolescence and young adulthood, so testicular cancer is the most common type of cancer in adolescence and early adulthood too. So it’s a tumour that affects a range of different ages of patients. The work we undertook was work looking at the microRNA profiles, which are short pieces of genetic code, and we did that in children’s germ cell tumours. What we found was a very, very characteristic signature whereby eight microRNAs from just two microRNA clusters were expressed at very, very high levels. When we did further work we found that that happened both in paediatric children’s tumours as well as the adult tumours, it occurred regardless of where the site of these tumours occurred in the body, so whether that was in the gonads, the ovaries or the testes, or at extra-gonadal sites in the body, such as the abdomen, the chest or the brain, and regardless of what the malignant subtype of the tumour was and that was the first universal finding, molecular finding, in this tumour.

That gave us a number of options in terms of diagnostics and therapy. One was to look in the bloodstream and find that these microRNAs were at a high level and that’s now gone from a single description of a child that we did five years ago to now over 1,000 patients described at the utility of this in the blood at diagnosis for disease monitoring and for relapse. So that’s one aspect about diagnostics and the other aspect is saying well actually if these microRNAs, these short pieces of genetic code and they’re very specific, they’re very high levels in the tumours, could we target that and use that as a target for novel therapy? That’s where, the latter half of this, is where the Children with Cancer UK grant has come in. What that has funded is work looking at using short pieces of genetic code to block the action of those high levels of microRNAs in malignant germ cell tumour cells in the lab.

Have you had any promising results so far?

It’s important when we do the test that we look at a range of different molecules and they’re modified in lots of different ways. Some of them are modified by having a stronger backbone, by increasing the number of bonds between molecules in the RNA molecule; some of them are adapted by having a peptide added on to them. So we’re looking at the moment at lots of different ranges of molecules and they seem to have an effect on affecting the growth of the cells. What we’re trying to do is find the best way where we maximise the effect on the growth rates but minimise toxicity to the cells because if we’re going to transfer this into use for humans in the future it’s important that that doesn’t have what we call off-target effects on other organs in the body such as the liver, the heart, lungs, kidneys etc.

So that’s ongoing work at the moment and we’re still analysing what the different types of molecules and which one would be the best combination to use to block these very high levels of microRNAs.

What do you think might be some of the impacts of this on children with cancer?

Overall the outcomes for children with malignant germ cell tumours are actually very good. So it’s opposed to some diseases where the outcomes are poor from first line therapy, the majority of children will actually receive treatment and do very well. So there’s a number of avenues to explore. One is for children, and also teenagers, young adults, who we identify as having poor risk tumours; some of those patients have an event free survival of as little as 50%. So in high risk patient groups there’s the possibility to develop these and use these sorts of novel agents potentially as first line therapy. There’s been a number of randomised controlled trials in poor risk germ cell cancer over the last thirty or forty years and very few of them have shown any benefit of just escalating conventional chemotherapy treatment. So we have to be more intelligent about the way we approach these patients and one way of doing that is to consider whether you use standard conventional chemotherapy agents alongside a novel agent. I think it’s unlikely that some of these novel agents will be used on their own but they may be used alongside conventional chemotherapy agents or be used with reduced levels of conventional chemotherapy agents which then may reduce the side effects of treatment. Because although most children are cured and do very well, there’s the long term effects when you treat these children and teenagers, young adults, at a young age include second malignancies, lung toxicity, kidney damage, an increased risk of cardiovascular problems such as heart attacks and strokes perhaps thirty or forty years down the line.

So that’s still, in terms of the type of tumour that we’re treating, the age of the patients when we treat them, is side effects that are happening in their thirties or forties, not in their sixties or seventies. That’s still got an important impact on those patients and also wider health economic impacts too.