A Cancer Drug That Prevents Seizures & More - Pablo Casillas-Espinosa, Monash Uni, Australia
A compound designed to treat prostate cancer appears to be effective in treating temporal lobe epilepsy in rodents - including the cognitive and psychiatric aspects so commonly accompanying seizures! Hear more from Pablo Casillas-Espinosa!
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Reported by Torie Robinson | Edited and produced by Pete Allen.
Epilepsy Sparks Insights episodes are meant for informational purposes only, and not as clinical or medical advice.
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00:00 Torie Robinson
Fellow homo sapiens! Welcome back to Epilespy Sparksk insights. So we know that anxiety, depression, and memory challenges are very common amongst those with temporal lobe epilepsy specifically, and of course these can be exacerbated when seizures are not controlled. Well, scientist Pablo Casillas-Espinosa has discovered that a drug for prostate cancer can remove not just the seizures in 75% of rodents with temporal lobe epilepsy butt also significantly improve their mood and cognitive function. It really is exciting stuff.
Please do remember to like, comment, and subscribe to the channel so that you get notifications of our episodes each week (!) - and now, let’s meet our absolute star of the week, senior research fellow, scientist, and Lab Head, Pablo Casillas-Espinosa.
00:58 Pablo Casillas-Espinosa
Oh, hey, Torie, thanks so much for the opportunity to share what we do. I'm, I mean, I'm excited to be here. Um, so I'm Pablo Casillas-Espinosa, I'm a trained clinician, but I work mostly in doing basic, uh, epilepsy research. I mean, obviously, we don't like the term “basic2 - we like to call it “fundamental translation” because it's not basic at all I should say (!), and I'm based at, uh, Monash University in Melbourne, Australia.
Yeah, so we work a lot on, I think the main purpose of my group is finding novel disease-modifying therapies in epilepsy. And you know, I suppose that we can talk about disease modification because that's the whole idea of the focus on my group. But I mean, the disease modification, the way we see it is to modify the epileptogenesis process, to modify how epilepsy - first, you know, the idea or the scenario: if we can modify or prevent the development of epilepsy, that will be, you know, the fantastic goal, the holy grail (!), but also not forgetting to do disease modification once epilepsy is established, because I think that's more applicable for people that, you know, have epilepsy or have drug-resistant epilepsy. And the idea is finding novel therapies or interventions that can sort of reverse that epilepsy process, that if you have, you know, if you are already diagnosed with epilepsy, you're taking a few ASMs, then potentially you can take a new intervention that [enables] you stop your ASMs and your seizures, but not only the seizures, but also other comorbidities, any cognitive problems…
02:34 Torie Robinson
Mental health.
02:35 Pablo Casillas-Espinosa
The idea of disease modification is not only focusing on the seizures, but focusing on comorbidities and again, mental health, a lot of stress and cognitive deficits as well, and cardiovascular, hair, and bone health. So there's lots of things that we can sort of improve by using the disease-modifying therapies. And sort of the idea of disease modification is that you take an intervention and then it stops the process. And ideally, you should not be taking any more medications because you don't want to have compounding adverse effects from taking one or two pills, so that's something we're aiming for. It may sound a bit too sci-fi, but we have great preclinical data and that's in different animal models that this is possible. And I think something we're really excited [about] is that we are now translating some of those results into a clinical trial.
03:32 Torie Robinson
That is exciting. And so this, I understand from our chat before, this trial's plan to last about five years: you want to get people from all around Australia involved. And could you just tell us the interesting story - just going back a little - about from where this idea for this treatment came from? Because I have reason to believe it wasn't necessarily targeting the brain initially, is that right?
03:55 Pablo Casillas-Espinosa
Yeah, exactly. And I think something, you know, when we are sort of developing drugs, like, you know, the path to create a new drug, a new treatment, it can take, you know, 30 or so years. But sometimes the compounds might be there. But it's just a matter of finding out whether they target any specific pathophysiological mechanisms for epilepsy. And this was something interesting because it was a drug that was developed by Chris Hovens from the University of Melbourne. And the idea was to use that drug for prostate cancer! But as the study progressed, they found out that it's a drug. It's called sodium selenate and it targets the phosphorylation of tau. And tau is everywhere in the brain. It rules lots of things that happen in the brain: not only neurodegenerative diseases such as Alzheimer's, Parkinson’s, and others, but also there's evidence in drug-resistant epilepsy, particularly temporal lobe epilepsy. So that's how we sort of took that approach: from going using a drug that affects mechanisms that are important in the brain, just to sort of taking that idea and see what would happen in animal models. And I think it's interesting, it's a completely different field, but I think it's quite important because instead of going back another 30 years to try to find a drug that may target tau, you [discover that you] already have it! So might as well use it! But obviously, it's not as simple as that, there's been lots of, I don't know, probably like 10 years or so of studies that we have realised that, yeah, this drug seems to be fantastic for epilepsy. I don't think it quite worked that well for prostate cancer, but now it seems that it's a great disease-modifying agent for temporal lobe epilepsy.
05:41 Torie Robinson
So a drug targeting going from bumhole to brain. And that's an interesting one.
05:46 Pablo Casillas-Espinosa
Yeah, yeah. Great story, isn't it?
05:50 Torie Robinson
It is! Yeah, remember that everybody: If you wanna tell the story to anybody “From bumhole to brain”, and then talk about this drug that is being developed!
And so, well, actually, is this drug a drug? Is it something gene modifying? What exactly is it? And how, simply put, how does it kind of work? Or may it work, should we say?
06:12 Pablo Casillas-Espinosa
Yeah, so yeah, it's interesting because it's a selenium compound, but obviously, it's very different from any selenium cells that you can get out there. And I suppose that selenium, it's important in the body, but it can be highly toxic, but the way it's selenate, it's more to a level in the brain, so in the brain and in the whole body. So you can take a bit more, sodium selenate and not having any nasty effects of selenium and other selenium salts. So that's why it's important that if someone is listening to this, don't go and just buy selenium or selenide because selenide is actually much more toxic than selenium. So it's really important that people just don’t go and “Oh yeah, I'm just going to get selenide or selenate over the counter”. Obviously, it's very different. But one of the things that we started looking at, at sodium selenide, was on the modification of the phosphorylation of tau. So, you know, tau is a structural protein. It's present all throughout the brain. The neurons need it for transport of, of whatever happens in one side of the neuron to the other, communicating one neuron to another. So without tau, you know, you essentially can't, your brain cannot function. You cannot do any, many simple things. So, because it gives a structure, if tau gets phosphorylated, it sort of helps move things in a neuron: imagine it's just like getting a hand moving things from one side to the neuron to another. It's just sort of like a train track, if you will! And that's by phosphorylation and dephosphorylation. But if tau gets too much from one thing or too much from the other thing, it stops functioning as anything in the body. And that's what we thought it would be the main mechanism. I mean, it is one of the mechanisms that it changes the phosphorylation of tau, but when we look at all these sorts of advanced molecular techniques that we look at different layers: so, you know, your body, you have genes, your genes generate RNA, the RNA tells your cells to generate proteins and the proteins may also generate some metabolites of those proteins. So that's, you know, that's what happens in a normal body and also in someone that has a disease. And when we look at how selenide would work, we find out that it was not only that, but it affected other really important processes including metabolism and including other cool receptors related to modulation of signals in the brain. So it seems that it's not only that, it's a more complex process and maybe that's one of the reasons that we are actually seeing that it modifies epilepsy because it not only… I never believed that there was going to be for this type of epilepsy (like temporal lobe epilepsy) I never thought that a single protein or a single gene would be the answer because it's a really complex disease. So maybe that's one of the reasons we have seen this fantastic effect of sodium selenate.
09:11 Torie Robinson
Amazing. And do you expect for this treatment to, or do you hope for it to reduce or eradicate seizure or extra extracurricular activity alone? Or do you expect it to improve a person's mental health, cognitive function, movement? What are your expectations or predictions?
09:35 Pablo Casillas-Espinosa
Yes. So look, I think this is a really, really important question. And it's something that my group has been working on because we honestly don't think that seizures is the main [target] outcome. There's more in epilepsy than just seizures. And something that we have learned from this clinical trial [was] because something that we did with Dr. Lucy Vivage from Monash University was to talk to patients and find out what the things that the people with epilepsy actually care [about]. And surprisingly for us, but unsurprisingly, I suppose for people with epilepsy(!), is that seizures is not always the first and most important thing, particularly for people with temporal lobe epilepsy. So, you know, it was cognitive deficits and other mental health problems and other adverse effects from Anti-Seizure Medications. So, it's something that… that's why one of the reasons my lab is working on not only reducing seizures but also improving comorbidities. And when I talk about comorbidities, like you said, mental health, cardiovascular problems, bone health, and others. And so something, when we did this… so normally what you do with a drug, like either you start with your medical chemist, then you go to cells, then you go to animal models, and then lots of things with animal models and small studies with patients and then large scale studies. So something that we did in our animal models (and we focus [on this] a lot) is looking at comorbidities as well because in animal models you can evaluate (which is something you cannot do in cells at least at this stage in time). So we look at comorbidities such as cardiovascular comorbidities, we look at as well as bone health. And there's a specific test that you can use in animals to evaluate, for example, the depressive-like behaviour, anxiety-like behaviour to see if they have any mood disorders, or [we take] some measures of mood disorders in animals. I know it's not exactly the same as in humans, but it gives you a good measure and good understanding whether it may work in humans or not, but also looking at cognitive deficits. You know, you would see an animal, you put them on a test and it's very clear that the animals that have temporal lobe epilepsy that is drug-resistant to treatment, they forget simple tasks. So you teach them how to do stuff and the animals don't do it. For example, there's studies on touch screens. It's just like little iPads that you get them to do the touch screen and then they receive something sweet and then they don't remember that they had to touch to receive some stimulus. There's another study that we do that you put them to different objects and they're like really curious. They look at, oh, okay, this is cool, this is new. And then if they have drug-resistant, uh, temporal lobe epilepsy, they don't realise that there's something new, or they forgot maybe that there was something new. So there, so there's ways that you can assess cognition. But anyway, just going back to that study, we look at all those things, um, on sodium selenate and in animals and we found that, yes, it stopped the animals from having seizures! So you give them the treatment and then after a few, what was that… I think it was about 12 weeks or so: the animals stopped having seizures altogether! So you did not have to give them any treatment at all in 70% of them, 75% of them.
12:58 Torie Robinson
Did the other things that you just mentioned, so cognitive deficit, was that you know, was their cognitive ability improved at all their memory or anything like that?
13:07 Pablo Casillas-Espinosa
Yes, so their memory, the memory of the animals that received sodium selenate was as good as the animals that did not have epilepsy.
13:15 Torie Robinson
Whoah!
Pablo Casillas-Espinosa, continued
So you would not realise that, you would not see any difference between this group. And in fact, when we were doing the study, we were like “Why? It seems that I have more of the animals that are not having epilepsy. It just doesn't make sense!”. And then when we looked at the data (because obviously we do that blinded as we don't want bias in our study), we realised “Oh my God, this is just improving their cognition all the way to animals that don't have epilepsy!”.
13:44 Torie Robinson
And mood [improvement] as well, was it? And any, anything else?
13:48 Pablo Casillas-Espinosa
Yeah, so depressive-like behaviour, so that would be sort of mood disorders like depression. So it was not, you would not see them affected as well. Yeah, it was just fantastic! The other thing that it was quite interesting because we are interested in this sort of telomere length (a telomere length is a sort of surrogate marker of whether a treatment is working or not). The animals that had selenate, their telomere length was comparable to the animals that did not have epilepsy! And I know that telomere has been shown in the past by others that it could be a measure of aging, but also could be a measure of a chronic disease. So it's something interesting that we're sort of trying to investigate more and understand more. Maybe telomere is not only about aging, but also about your overall health condition. But we need to do more research because we don't understand exactly what's the mechanism about that. But I think, oh, yeah.
14:39 Torie Robinson
It’s amazing!
14:40 Pablo Casillas-Espinosa
No, no, and honestly, I think it's a great story.
14:43 Torie Robinson
And is this solely adults you're looking at or children as well?
14:46 Pablo Casillas-Espinosa
Yeah, so we are focusing on adults at this time. And that's normally the way you do it. If you have a drug that can be used for children and adults, you go first with your adult population. And then if it works, we realise the safety is great and we can target younger people with temporal lobe epilepsy.
15:08 Torie Robinson
Thank you to Pablo for his exciting work, and his true empathy for many with epilepsy - i.e. it is not all about seizures, plus his incredible research and results regarding temporal lobe epilepsy.
Again, if you haven't already, don't forget to like, comment, and subscribe, and see you next time.
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Pablo Casillas-Espinosa was trained as a medical doctor (MD) at the University of Guadalajara, Mexico, before moving to Australia to study his Ph.D. with Prof. Terence O'Brien at the University of Melbourne.
Pablo is a Lab Head of the neuroscience department at Monash University and an NHMRC Early Career Fellow. He has an impressive track record at this stage of his career with multiple publications and international presentations, many of which relate to the preclinical development of new epilepsy therapies and chronic animal models. He is an emerging leader in the field of epilepsy, biomarkers, and drug development within just four years of the completion of his Ph.D. (Top 0.50% Worldwide Epilepsy Experts, expertscape.com). His Lab group focuses on finding novel disease-modifying treatments and targets of brain diseases using multi-omics and computational approaches. Pablo's group uses a wide range of models of epilepsy, stroke, and traumatic brain injury, from molecular and cellular assays of neuropathology to neurobehavioural assessments and advanced neuroimaging techniques (MRI, DTI, PET). He has successfully obtained competitive grants, resulting in high-impact publications, one patent (PCT/US2017/000097), and ongoing clinical trials of novel therapies. Pablo has a growing international reputation, evidenced by his increasing number of international competitive prizes, awards, and invited talks. Pablo is involved in invitation-only committees of the International League Against Epilepsy (ILAE).
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NIH - Related paper: ncbi.nlm.nih.gov/pmc/articles/PMC10208637
Twitter: PabloCasillasE1
LinkedIn: pablo-casillas-espinosa
Monash Uni: pablo-casillas-espinosa
Melbourne Uni: pablo-casillas-espinosa
ResearchGate: Pablo-Casillas-Espinosa
ILAE: pablo-casillas-espinosa1
Orcid: https://orcid.org/0000-0002-6199-9415
Mirage News: monash-funds-3m-for-first-ever-epilepsy-drug