Brain Tumour-Related Epilepsy - Mark Cunningham, Trinity College Dublin, Ireland
Brain tumours commonly cause epilepsy. Learn more about research into Brain Tumour-Related Epilepsy with Mark Cunningham.
Reported by Torie Robinson | Edited and produced by Pete Allen
Podcast:
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00:00 Mark Cunningham
“But we're doing organotypic human brain slices. So what this means is that normally when we get brain tissue, we can keep it alive for probably around about 24 hours. There's a few tricks that you can use to kind of push it out a little bit further. But if you want to keep it alive for say, 7 days or 10 days (the kind of periods that you need really to get good transfection), then you have to use organotypic approaches.“
00:25 Torie Robinson
Fellow homo sapiens! Welcome back to Epilepsy Sparks Insights.
Now, this a bit crazy to me - that I rarely hear about people speaking of brain tumours and epilepsy in the same sentence! Because seizures and epilepsy are a really common side effect of brain tumours! Now, hear more today from the brill Mark Cunningham of the Cunningham lab at Trinity College Dublin in Ireland who shares with us the exciting research he is doing into brain tumour related epilepsy!
A quick one - please don’t forget to like, comment and subscribe. Your comment and like will help spread awareness and understanding of the epilepsies around the world.
Now, onto our star of the week, Mark Cunningham.
00:57 Mark Cunningham
I'm the Ellen Mayston Bates Professor of Neurophysiology of Epilepsy and I'm based in the discipline of Physiology in the School of Edison at Trinity College Dublin and I did my PhD, gosh, a long time ago now in Bristol with Roland Jones. I was looking at Anti-Seizure Medications and how they altered synaptic transmission in the brain. And then I went off and spent some time looking at neuronal oscillations, brain waves, and kind of got back into epilepsy through that, looking at high frequency oscillations. And I've done some work with Roger Troub, who's a computational modeler, looking at the mechanisms behind those. And then I went to Newcastle and I spent 13 years in Newcastle. And [it was a] very exciting time in Newcastle. I set up a platform to do recordings in human resected brain material (from patients with refractory epilepsy) and I suppose that's kind of informed a big part of my research since then is trying to use human material from epilepsy patients, combining that with electrophysiological techniques, pharmacological techniques, to try and understand how networks in the brain generate certain types of epileptiform activity and then if we can get a better understanding of that, can we come up with better ways of treating the condition and in particular the sort of the seizure activity associated with the condition.
02:36 Torie Robinson
And do you focus on specific types of epilepsy?
02:39 Mark Cunningham
So a big focus of the lab at the minute is Brain Tumour-Related Epilepsy. So, you know, getting a tumour is a pretty… - [a] brain tumour is a pretty significant diagnosis for a lot of people. And a lot of patients who have a brain tumour will usually, well one of their presenting symptoms may be a seizure. So then they go and get a brain scan and of course, they'll get the very upsetting news that they have a tumour, but also a significant proportion - somewhere around about 30 to 40% - will also have seizures and will develop epilepsy. And so there is a condition now called Brain Tumour-Related Epilepsy. And so we're very interested in that. We're very interested in understanding the mechanisms that underlie that.
We're particularly interested in a neurotransmitter called glutamate, which, you know, as you know, excites neurons. And what seems to be occurring in these brain tumours is the tumours like to produce glutamate. They love to produce glutamate. And the tumours are, I mean, they're pretty, sort of, it's a pretty insidious mechanism in that they actually use the glutamate to not only to promote their growth, but also to allow them to kind of move out and occupy new space. So they produce lots of glutamate and the glutamate gets to such high levels that it will kill neurons. And the glutamate also feeds back onto the tumour cells and makes them grow and move and occupy the space where the neurons used to be/the brain cells used to be.
Now, of course, too much glutamate is also going to excite neurons and it's going to cause them to generate seizure activity. And every time you have seizure activity, you also get more glutamate! So it's a really sort of, sort of insidious kind of feedback cycle. So the kind of tumour has hijacked the glutamate system to kind of promote its own growth, but also to promote seizure generation as well.
04:58 Torie Robinson
What you're looking at is, is it the activity of the brain whilst the tumour resides, or is it afterwards, or is it both?
05:08 Mark Cunningham
So it's probably, it's a kind of, I mean, how we study it at the minute is we, again, work with neurosurgeons here in Dublin at Beaumont Hospital. Some of these patients will have their tumour removed and there'll be a part of the surrounding brain tissue that's been infiltrated with the tumour cells - we will get that. So I often refer to this as a kind of badlands where you kind of have these kind of nasty, infiltrating glioma cells, rubbing up against kind of, you know, brain cells. And it's that interaction. And what we see in those samples is we see seizure activity because there's probably too much glutamate and that's exciting these neurons. So we're trying to work on a way of potentially treating that at the minute.
We're funded by Science Foundation Ireland. And this work takes place as part of the FutureNeuro centre which is an SFI funded centre. And we're actually trying to use a novel gene therapy approach. So we're trying to target the brain cells with a particular channel that's activated by glutamate. So, because there's too much glutamate, when the glutamate acts on this channel (that we've expressed in the brain cells (it will actually turn off those brain cells that will quieten them down). And so we're hoping that might be a novel way of treating seizures that are seen in Brain Tumour-Related Epilepsy.
06:42 Torie Robinson
What this sounds like as well, as if you quieten down those cells, then you're effectively protecting the undamaged (so far) cells as well.
And how far along are you in this specific part of your work and where in the process of the whole study?
06:57 Mark Cunningham
So when I arrived in Dublin five years ago, the first thing to do was to get ethics set up because obviously you have to have ethics in place to do the human element of this work. And I was in the process of doing that and then COVID came along!
07:13 Torie Robinson
Oh yay, “great” timing.
07:16 Mark Cunningham
And yeah, so COVID kind of slowed things down a bit because of course a lot of ethic committees were very focused on COVID related projects. But we're up and running now. We've been going for about a year. So the human recordings are going.
A big part of this project is also an animal model. So we're using an animal model in which we express tumour cells and then they grow brain tumour. And for that part of the project, what we're doing is… so the human bit is ex vivo in vitro brain slices. The animal part is in vivo. We're actually doing EEG recordings and it will be like video telemetry. So these mice will have wireless recording system electrodes, we'll record the seizure activity as the tumour grows and we'll be video monitoring them so we can, you know, capture the seizures. And then the idea is that we would run a sort of clinical trial almost where we would compare animals that have had the gene therapy approach versus untreated animals.
And then the ultimate goal is to translate that into the human brain slices. Now, that's a little bit more tricky because with the gene therapy, you need an amount of time so that the cells actually start to express the channel that the gene is expressing in. But we're doing organotypic human brain slices. So, what this means, is that normally when we get brain tissue, we can keep it alive for probably around about 24 hours. There's a few tricks that you can use to kind of push it out a little bit further. But if you want to keep it alive for say, 7 days or 10 days (the kind of periods that you need, really, to get good transfection), then you have to use organotypic approaches. So that's where you take the slices, you keep them in a very special brain juices, I call it (!) and you stick them in a special incubator and they cook away for you and you can keep them alive for, you know, for sort of weeks. And that gives yourself enough time to get the viral vector in there and express the genes in your cells.
09:33 Torie Robinson
Oh goodness. And so what will, what do you reckon like, well, when [shall] this project officially end? And like in funding wise and stuff?
09:42 Mark Cunningham
Funding-wise, it's got another, another couple of years, another two years. So we're hoping that by the end of the project, we have a very good body of, you know, both preclinical animal work, but also proof of concept in human tissue as well. And I think then we need to think about sort of probably… the next step in terms of you know, thinking about maybe testing this in a larger animal model.
But the human, I mean, one of the things that always really excites me about human tissue work is that you really are that much step closer already in terms of using patient-derived material! And this is material that's come from the patients, you know, you've got these slices, these slices are generating seizure activity, we're able to record them, you know, we can record them with an individual electrode, we can use Multi-Electrode Arrays, and what, you know, we're doing in those tissues is: we're not only doing the gene therapy work, but we're also looking at other novel compounds and trying to understand whether, you know, there's other approaches that can be used, again by targeting, you know, particular glutamate receptors. And if you can prove that, if you can demonstrate efficacy, albeit in a reduced model, but albeit a human model, I think that gives a lot of confidence that, at least the mechanism of action stands up. Now, of course, when you develop drugs, there's lots of other problems and issues, but I think it's being able to demonstrate Mechanism of Action and efficacy, which is very powerful in human pathological tissue.
11:35 Torie Robinson
Often if it works in a mouse model, that's great, or zebra fish - that's also great, but the fact that you are actually using human tissue and to see the impact, that is pretty amazing
11:47 Mark Cunningham
Like, I don't get in the lab much, but I love, kind of, you know, get into the lab for that.
11:52 Torie Robinson
Pretty exciting!
11:47 Mark Cunningham
It's very, you know…I often say, you know, we're very, very lucky to be doing it. And obviously, you know, we have enormous gratitude to the patients that consent so that we can use, you know, the material in this way. It's such a unique resource. And I always say to the guys that are working with the lab, you really have to maximise what you get out of this because it's such a valuable resource. And it gives us such unique insights. And, there's not many places around the world that are doing it! So it’s, you know, I find it extremely gratifying as a scientist to be able to do that kind of work.
12:36 Torie Robinson
And you know, my experience, maybe it's just my experience, but when it comes to the epilepsies amongst people who've had a brain tumour (and the epilepsy is a result of that), it's really not spoken of that much at all! It's a common trigger for epilepsy if you have a tumour of any kind, whether it's cancerous or not, right?
12:55 Mark Cunningham
Yeah. And it's and that's a very, very good point. You know, again, we think a lot and we think a lot about the gliomas, which are the invasive tumours. But it's also the case for meningiomas (which are, you know, the tumours that affect the meninges). In that case, what happens is you get physical pressure down on the brain rather than an invasive process,
13:22 Torie Robinson
Oh, yeah, so it squishes it basically
13:25 Mark Cunningham
It kind of squishes it, yeah.
13:26 Torie Robinson
Yeah, the professional term.
13:26 Mark Cunningham
But it still will, that will still cause seizures. So, yeah, I think, I do think it's changing. There's a number of people who are, you know, are working in this area now. There's a lot of good groups in the UK and in Italy as well - that are very interested in Brain Tumour-Related Epilepsy. So, it's definitely there. I think that, I think the difficulty lies in that it's kind of, it's ...it's maybe sort of stuck between two stools because it's neurology and it's oncology. And so, you ,now, you have this kind of area, it's “neuro-oncology”, but I think there's a lot of interesting work now that's happening and there's some amazing work, for example, that's coming from, there's a lab in Stanford, the Monje Lab. Some of the work that they're doing is really incredible in this area as well.
14:23 Torie Robinson
It’s lovely that you mention these other labs because I think more and more now labs are working together, right, sharing where possible so as not to faff about too much and do the same thing more than times than is needed etc.
12:37 Mark Cunningham
Yeah. Well, I mean, I think, you know, when you look at these, the work that other labs are doing as well, it's quite inspiring! You know, sometimes it's a bit like, oh, damn, you know,
14:46 Torie Robinson
They did it first, argh!
14:48 Mark Cunningham
They’re beating [us to] first [place], you know, but it is great, you know, and I mean, just thinking I've got a, you know, there's a, there's a lab in Paris led by Gilles Huberfeld, who does a lot of work in Brain Tumour-Related Epilepsy and you know, Gilles and I are kind of great collaborators now, even though I probably, you know, and so he's visited Dublin and, you know, I'm on a P.h.D committee for one of his students. So, you know, these things should lead to sort of positive interactions and collaborations. You know, we can actually gain a lot from one another's work.
15:21 Torie Robinson
A huge thanks to Mark for sharing with us his exciting research into epilepsies caused by brain tumours and what the future may hold!
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Mark Cunningham is the Ellen Mayston Bates Professor of Neurophysiology of Epilepsy at Trinity College Dublin. He studied at Queen’s University, Belfast where he read Physiology as an undergraduate and he obtained my P.h.D in Physiology from the University of Bristol. After that, he worked in Bristol University, University of Leeds, Heidelberg University and Newcastle University. In 2005 he was awarded a RCUK Academic Fellowship at Newcastle University. In 2007, alongside Prof. Miles Whittington, Mark founded the first UK research platform for conducting electrophysiological recordings from live human brain tissue ex vivo in Newcastle with support from the Wolfson Foundation. In 2016 Mark was appointed as Professor of Neuronal Dynamics at the Institute of Neuroscience at Newcastle University and he currently hold a visiting Professorship at Newcastle University.
The Cunningham Lab is located in the Discipline of Physiology in the School of Medicine and they use a variety of electrophysiological approaches to study the mechanisms by which neuronal microcircuits generate organised electrical activity in the brain. Their research is focused on understanding the basis of neurological and psychiatric disease at the level of the neuronal microcircuit and in particular in the context of physiological and pathological electrical activity generated by the brain in certain disease states.
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X/Twitter: thebraindocMD
LinkedIn: briandlouhy
Cunningham Lab: cunninghamlab.org
Trinity College Dublin: mcunnin1
FutureNeuro: markcprofile
ResearchGate: Mark-Cunningham-9