The Festival of Genomics and Biodata is just around the corner, and we’ve had the opportunity to sit down with some of our expert speakers to get a sneak peek into what they’ll be discussing at the event.
This week, Sally George (Paediatric Oncologist and Group Leader, Institute of Cancer Research) reflects on the clinical experiences that fuel her research and explains how new technologies – from liquid biopsies to fragmentomics – are reshaping how clinicians diagnose, monitor and treat paediatric cancers. She offers a behind-the-scenes look at the SMPaeds2 programme and the collaborative effort required to bring genomic advances directly to children and families.
Please note transcript has been edited for brevity and clarity.
FLG: Hi everybody. Today, I’m here with Sally George, Paediatric Oncologist and Group Leader at the Institute of Cancer Research, ahead of her talk at The Festival of Genomics and Biodata in January. Sally, thank you so much for joining me today. How are you doing?
Sally: Yep, good. Thanks.
FLG: Could you start by telling us a bit about yourself and your career?
Sally: I’m an Academic Paediatric Oncologist. I did my PhD quite late in my career, after I was already a Consultant Paediatric Oncologist, and essentially from that point onwards, I have stayed predominantly in the research setting, sort of an 80/20 split. I did my PhD at ICR and then did postdocs at ICR and the Francis Crick Institute, before returning to ICR to set up my independent team.
I have two main streams of research. One is that I’m very interested in the common poor outcome solid tumour of childhood neuroblastoma, and we have a number of projects focused on the underlying biology and identifying novel targeted agents for neuroblastoma. And the second large chunk of my research is the translational biomarker initiatives for children with cancer.
FLG: And what first inspired you to focus your work on paediatric cancer, and things like liquid biopsy approaches?
Sally: I’m a paediatric oncologist, so my motivation comes from my clinical practice. My motivation into research really comes from the huge number of unanswered questions and the huge unmet need that we have in the paediatric oncology setting. For me, as I’ve said, my lab looks at slightly more fundamental biology as well as the translational research. And I think for me, the biomarker side of things keeps me much closer to the clinic, and you can see real time change and implement change, which is quite motivating for me.
FLG: What do you find most rewarding, and conversely, most challenging about working in translational cancer research?
Sally: As I’ve just said, being able to actually see real time change that’s actually affecting patients is definitely the most rewarding thing.
There’s lots of challenges. We work in very rare diseases, which means we have to collaborate really closely, not just in the UK, but across Europe. Which is fantastic, but it also comes with huge amounts of logistical hurdles, legal hurdles, ethical frameworks. All of these things are super important, but they can feel like blocks when you’re trying to advance the research quickly, and get these things into clinical practice. So, it’s the logistics that’s the most challenging.
FLG: And for those who may be less familiar with it, could you explain what ctDNA is and why it’s such an exciting tool for cancer diagnostics?
Sally: ctDNA stands for circulating tumour DNA. It’s essentially DNA that’s released from tumour cells into the circulation. All cells in your body will release DNA, as there’s a natural turnover and amount of cell death. But of course, if cancer cells are releasing their DNA into the circulation, we can take a blood sample and sequence that and identify mutations or other changes that are associated with that particular cancer. The reason why it’s so attractive is it’s much more accessible than tissue biopsy, which is the other way to get access to those samples. What we’re finding is we often use the term ‘liquid biopsy’, because what we find is that the DNA that we see in the circulation is much more representative of the tumour as a whole, not just the tiny part of the tumour that you’re sequencing. So, it has a lot of advantages, at least for now, as a complementary technology to tissue biopsy. And also, because it’s less invasive, we can do serial sampling. We can see how tumours adapt and evolve through treatment. So, lots of potential.
FLG: Are there any differences in how you would apply that kind of analysis in paediatric cancers compared to, say, in adult cancer?
Sally: The obvious difference is that children are much smaller than adults, so we often get less blood. We have to think about that when we’re developing assays that we want to use in the paediatric space. The other thing to say is that the mutations that we see in paediatric tumours are often quite different, so we do need to develop bespoke paediatric type approaches to make sure that we’re capturing the mutations that are important in the cancers that we’re interested in. I think probably the final thing to say is that overall, in general, we see fewer mutations in paediatric cancers compared to adult cancers. So, it’s really important we think beyond mutations when we’re developing ctDNA approaches, and that we’re looking at other ways in which we can infer the epigenetic state of cells, or find alternative methodologies to detect cancer signal, because we can’t rely on mutations as much as in other adult cancers.
FLG: That’s really interesting. In your talk at the Festival, you’re going to be discussing the Stratified Medicine Paediatrics 2 (SMPaeds2) programme. Could you describe what makes that programme unique?
Sally: I guess I’ll start with, there was obviously a Stratified Medicine Paediatrics 1 before 2. And so with SMPaeds in general, the whole programme is really designed to develop assays in the paediatric setting that are to clinical reporting standards from the outset, and to offer these within a research trial to children with cancer across the UK, but to transition them into NHS standard of care. So, within SMPaeds1, our sequencing panels were adopted by the NHS testing directory, and that’s exactly the aim with SMPaeds2, that we’re doing this to make these tests available as quickly as possible and to make them as accessible as possible. Although it is a research study, it’s very much looking at how we can implement these tests within standard of care diagnostics.
FLG: And your talk is also going to touch on fragmentomics. Could you explain what fragmentomics is and how you’re using it?
Sally: Fragmentomics is really a bioinformatic approach to look at ctDNA. And what we know is, when you have DNA that’s released into the circulation, the DNA that’s tightly wound around nucleosomes is transcriptionally inactive or silent, and then the DNA that is open and not wound around a nucleosome is active or actively expressed. And what happens is, because the DNA that is actively expressed is more open, it gets degraded by circulating nucleases. What that means is that we have a dip in sequencing coverage at the most active sites of DNA. We can use those patterns to infer which genes are active and being expressed and which genes are being repressed, just by standard DNA sequencing. So, when we did that in the SMPaeds1 programme, we had this really heterogeneous cohort of patients, and what we could see is by just looking at the genes that we thought were active, we could really identify cell of origin or tissue of origin, or transcription factors that we already know are very important in these diseases. It offers a way in which we can maybe help with diagnosis, but also with serial sampling in future studies, how we may be able to understand how these tumours adapt over time in response to treatments, and how they may change their transcriptional profiles without the need to biopsy.
FLG: That’s really interesting. And my next question was going to be a bit more detail on that. When you say you can use this for diagnosis and stuff, can you also use it to for, say, patient stratification, or for prognosis, or anything along those lines?
Sally: Hopefully in the future. For now, what we have is proof of principle that this technology works, and we need to do much, much more work to understand exactly how we could use this in a clinical setting. So yes, I hope for all of those things, but in time with further validation.
FLG: That sounds really exciting. And do you plan to incorporate any other modalities in the future? And if so, which ones would be most useful in this context?
Sally: Yeah, so within SMPaeds2, we have a whole pipeline, really, where there are certain technologies that we’re offering to patients with clinical reporting. ctDNA sequencing is one of them. The next one, which we hope will come online during the course of the programme, is Nanopore sequencing of tissue samples. But then we have a whole suite of methodologies, both on blood and in tissue that are being evaluated in the research setting within SMPaeds2. The hope being that we really have this pipeline where we robustly evaluate technologies in the research setting, and we get them to where we can begin to prospectively report on the results before downstream implementation. The clinical side of SMPaeds2 is offering liquid biopsy sequencing, above and beyond standard of care tissue sequencing. Nanopore sequencing will come online, but then there’s everything else that will come further down the line, hopefully.
FLG: To go back to something that you mentioned earlier, you said that a complexity of working in paediatric cancers is that children are smaller, you can get less blood. ctDNA itself is generally low abundance, so how do you deal with those challenges?
Sally: It is a challenge. Although children are small and we get less blood, there are certain types of childhood cancer where we see huge, huge amounts of atDNA, and this is because children’s cancers, or the ones where we see huge amounts of ctDNA, they’re often very aggressive, very rapidly growing, highly metastatic tumours. So, actually, in diseases such as high risk neuroblastoma, we see huge amounts of ctDNA on just a tiny blood sample. But there are other tumour types where we see much less ctDNA, the obvious example would be paediatric brain tumours. So, as well as a general paediatric cancer approach, we’re going to need to develop specific methodologies for certain subtypes of cancer where we have a much lower abundance of ctDNA, and we need to be looking at much more highly sensitive methodologies in these specific tumour types moving forwards.
FLG: It sounds like there are a lot of complexities, but how close are we, in your opinion, to seeing these ctDNA based approaches used routinely in paediatric oncology?
Sally: Pretty close, I would say. We’re doing ctDNA panel sequencing and reporting it within SMPaeds2, and increasingly, there are clinical trials that will allow ctDNA mutation detection for enrollment into a clinical trial of a targeted agent, so that we’re pretty much already there. I think the nuance and the complexity will come for using the serial ctDNA sampling for monitoring, for relapse, or disease assessment, and we need much more disease specific information to know how to interpret that data. An example of that is within the neuroblastoma world, we are working on opening an EU funded clinical trial called Mona Lisa, which is specifically for neuroblastoma, to see if we can understand how to integrate the serial liquid biopsy for detection of disease burden into clinical practice. So, we will participate within that study within the UK. I think in terms of mutation detection, we’re there pretty much. We’re already understanding, ‘what’s a positive signal? What do we report? What indicates disease relapse?’ In very disease specific contexts we will require large scale international collaboration in the individually rare diseases.
FLG: Well, that’s really exciting to hear. How do you see this kind of approach shaping the future of precision medicine for children with cancer?
Sally: In many ways, the obvious ways, more accessible genomics and sequencing to match more children to targeted therapies. But I think these technologies also have a real potential to help us better understand the biology of these tumours. The potential to take serial samples, to really understand how these cancers are adapting and changing, and then, of course, to develop treatments to target the ways in which these cancers are drafting, adapting and changing, is really exciting. I think it will absolutely change both forward translation, but also reverse translation, in terms of understanding biology and driving the next generation of targeted therapeutics as well.
FLG: This is a bit more of a personal question, but what do you find most meaningful about working in research that directly impacts children and their families?
Sally: As I said at the beginning, my drive comes from my clinical practice. I worked as a full time clinician for about 13 years before I started my PhD and went into research. And there’s nothing like working on a paediatric oncology wards, day in, day out, to give you motivation to try to implement change into clinical practice. So, my motivation comes from my clinical experience, and it still does. I only have a 20% clinical role at the moment, but you know, I can just spend a morning in the hospital, and it reminds me exactly why we need to do all the other things that we’re doing.
FLG: I’ve got a couple of final questions for you. As I mentioned earlier, you’re speaking at the Festival of Genomics and Biodata in January. What are you looking forward to about the event, and why would you encourage people to come along?
Sally: I’ve never been before, and I’m really excited about going. It’s a huge conference, probably the biggest conference that I’ve ever been to. What I’m looking forward to is learning about core new technologies and then understanding how I can implement those into my own research. And in terms of encouraging people to come along, to have that amount of information and that many really eminent speakers available all together within one venue, why wouldn’t you go? I’m sure there’s plenty to learn, plenty of opportunities to develop collaborations and I’m looking forward to it.
FLG: If there’s one thing that you would hope the audience will take away from hearing your talk, what would it be?
Sally: Oh, that’s a difficult question! I think the most important take home messages are that if we are to truly implement research into clinical practice, we have to be systematic, we have to be collaborative, and we have to really work together across multiple disciplines from an early time point.
FLG: That’s great. Thank you so much, Sally, we’re really looking forward to seeing you in January at the Festival.
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