Episode 55 - Spotlight on Research into Glioblastomas

In this episode, Chandos talks to one of our Future Leaders Dr Angel Alvarez-Prado. Angel is a highly accomplished researcher at the University of Lausanne in Switzerland where he is currently working on the innovative perspective of simultaneously targeting both cancer cells and their supporting immune microenvironment in the hope of finding more effective treatments for glioblastomas. Angel explains what his research involves and how it may help people diagnosed with glioblastoma in the future.

You can read more about Angel and his research here
You can find out more about the research we fund here

You can contact our Research team by emailing  research@thebraintumourcharity.org or phoning 01252 418190.

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Transcript

Unknown: 0:28

Music.

Sarah: 0:38

Welcome to Let's Talk about brain tumors. The podcast where we'll be talking to people who've been affected by a brain tumor diagnosis, either their own diagnosis or the diagnosis of a loved one. We'll also be sharing news and updates on The Brain Tumour Charity about what we're doing to have the harm and double survival.

Chandos: 0:56

Hi everyone, and welcome back to The Brain Tumour Charity podcast in this spotlight episode, we speak to a researcher about their work into looking into how we treat glioblastomas, what more can be done to help patients who have a diagnosis. I found this, this episode, really insightful. I hope you do too. If you have any questions, please feel free to reach out to the brain tumor charity, direct or visit brainchimacharity.org, for further information. Do you want to talk about yourself and your role as a researcher?

Unknown: 1:25

Sure. Yeah. My name is Angel Alvarez-Prado. I'm a postdoctoral fellow in Johanna Joyce’s lab. I joined the lab in 2019 and since then, I've been focusing on understanding the biology of the tumor immune microenvironment in brain cancer. So this is all the cells that form part of the tumor bed, that sit within the tumor, but are not cancer cells, so immune cells, fibroblasts, vessels and other cells. So our work is focusing on understanding the biology of this component to try to find new ways to manipulate it for therapy

Chandos: 1:58

How does the research that's being funded by The Brain Tumour Charity help Brain Tumour patients specifically?

Unknown: 2:06

So yeah, that's that's very important question. So the project, they got funded by the by the future leader programs from from the charity focuses on glioblastomas. Glioblastomas are primary brain cancers, and the challenge with these tumours is, first of all that there is high mortality. They affect a lot of people. It's estimated that around 15,000 new patients will be diagnosed per year in Europe and the US and the treatment unluckily, it invariably fails. So the median overall survival is around 15 months. And therapy never eradicates, or very rarely eradicates completely the disease. And there are many reasons for this. So first of all, of course, the location of the tumors is very challenging. So even when the surgeon removes the tumour, these tumours tend to be infiltrative, so it's very, very difficult that the surgeon will be able to remove all malignant cells. There is a second challenge, which is that this these tumours are extremely heterogeneous, which means that different tumors from different people will behave differently and respond differently to therapy, but even more, within the same tumour, we can find different regions in the tumors or different cells. So these units that will compose the tumour that they're also different, which makes it extremely challenging to only have one one therapy that will kill all the different kinds of cells. And then the last challenge associated to the treatment of glioblastoma tumors is that the tumor microenvironment, and specifically the immune microenvironment, so all immune cells that are part of the tumour bed is immunosuppressive, which means that it's contributing to tumour growth, to tumour progression and to resistance to therapy. So there are several challenges that we that we need to tackle if we want to find new therapies for glioblastomas. And this is what I wanted to do in the project that I proposed to the brain charity. So what my project is trying to do is to target an innate immunity checkpoint, to reprogram the way in which cancer cells talk with the immune microenvironment, with immune cells in the microenvironment of these cancers. And the idea here is that by reprogramming this communication, we will prevent cancer cells from hiding from the immune system. Because what happens now is that cancer cells are smart enough to cheat the immune system and to hijack it for their benefit. So they are basically saying, Look, I'm not the bad guy. I'm the good guy, so don't attack me. Help Me Grow. So what we want to do by targeting this innate immunity checkpoint is to actually unhide, let's say, cancer cells from the immune system, to actually make tumor cells the immune system look on the I'm the bad guy. You should be attacking me.

Chandos: 4:44

And this research is over a number of years. And where are you in? Are you sit in the planning phase. Whereabouts are you in in terms of the research and development of the program?

Unknown: 4:54

Yeah, so this research has started now almost five years ago, and the project that that was funded by the by the charity, it's actually an extension of the project. So based on some very promising preliminary data that we got, we decided that we wanted to expand it further and evaluate this strategy of targeting this innate immunity checkpoint in combination with other immunotherapies and with other standard of care modalities. So we started this one year ago now, so this extension of the project, but we already have some results that. Really indicate that targeting this innate immunity checkpoint can be a valid way to treat glioblastoma tumours. This, of course, needs to be taken, taken with a pinch of salt, because we are doing this in preclinical mouse models of glioblastoma. And so far, what we have seen is that actually targeting this pathway is leading to extended survival in these models, the tumours grows lower. So it's very, very promising, but we need to be very, very cautious, because we know there are many examples in other cancers, in glioblastoma as well, in which very promising results in preclinical mass models do not necessarily translate into a clinical benefit. So of course, we would like to get there, and that's the idea, and that's why we start this, project, because our ultimate goal was to improve the therapeutic options for for glioblastoma patients, but we take it step by step and be cautious. So now we're at a point in which we know that this can be a valid approach. We are trying to understand better. What are the mechanisms by which this is happening. So why are cancer cells growing slower? Where this clinical mass model survival surviving longer when we when we treat them and when we target this pathway that I mentioned before? So I think it's it's exciting. We're at a very exciting point, but we also need to be realistic and know that probably from now to translation, there is still a good 5 to 10, years.

Chandos: 6:56

And you said there that the research you're doing sits alongside other treatment models that are already being used. So it's the goal for the research that we're doing not to find necessarily one single cure, but something that sits alongside the existing models of treatment, such as radiotherapy, chemotherapy, to to really enhance the standard of care.

Unknown: 7:18

So that's one of the things that we actually wanted to evaluate in this project. Of course, if we would just be able to cure glioblastomas by targeting this this pathway, that will be fantastic, but this is extremely unlikely. And would we see in our preclinical mass models is not complete remission, what we see is extended survival and reduced tumour growth. So this is telling us that we really need to combine this with other therapies, as you were asking, and that's exactly what we are evaluating. We're evaluating combination of targeting this pathway, of this this protein, specifically, it's called later one. I can give you more details later. And we're combining this with radiotherapy, and we are combining it with other immunotherapies, immune checkpoint blockade and another drugs that can somehow also reprogram the immune microenvironment. So the idea here is to really engage the immune system to fight these tumors, so that we can combine therapies that are targeted against cancer cells alone with a therapy that is going to reprogramme the immune system to fight also cancer cells. So in this way, we'll be having this to hit approach, let's say in which we are triggering mechanisms that will lead to cancer cell death from the cancer cells themselves. That's what radiotherapy, for example, does, or chemotherapy. But at the same time, our aim is to also be able to engage the immune system to attack these cancer cells, so we can have both simultaneously, and hopefully we can have more durable responses.

Chandos: 8:48

When we talk about brain tumors, we know that they can affect people very differently. How does that affect your research? In terms of, do you find any any mutations in the tumour types? That then means that you have to adapt your methodology or the way you're doing the research?

Unknown: 9:05

Yeah, that's an excellent question, because, as I was mentioning before, glioblastomas are very, very heterogeneous, and one of of the sources of heterogeneity, it's mutations as you, as you're as you're indicating. And something that is very interesting, and that we found in in our research, is that when we target either one, when we are targeting this innate immunity checkpoint, and we have done this, for example, in different glioblastoma cell lines coming from different patients with different mutations, this treatment is effective in all of them equivalently, because we are targeting a mechanism that is present in all cancer cells, regardless of the genetic makeup, regardless of the transcriptional subtype to which they belong, regardless of many other components of this huge heterogeneity that we mentioned before, and that's why we think that that can be a very valid approach to in the future, develop new therapies, because we believe it will help us overcome this huge heterogeneity. Because so far in our hands, also in mouse models, we have generated four different technical mouse models of glioblastoma, also recapitulating different subtypes and tumours with different mutations, and in all of them, we have found exactly the same results. So we see this extended survival, which is indicating that by targeting either one, we can really, I cannot say, completely overcome the heterogeneity of the disease, but at least this is providing a good start. Starting point to find a therapy that, in principle, should be effective regardless of of this genetic and ascription heterogeneity.

Chandos: 10:36

And how are you involving people with lived experience of of brain tumors involved in your research? So we previously spoke to a researcher who's they were looking at the the kind of the aftercare and and the way that we support people once they have a diagnosis, how are you involving people in the research that you do and making sure that they're taken with you on that journey?

Unknown: 11:00

Yeah, so unfortunately, I'm not very close to patient care. So what I'm trying to do is just to disseminate what we do, how we do it, the reason why we do it, and we were finding. So I'm trying to make our research accessible to people, to patients, of course, but also to people involved in patient care. So for example, nurses, doctors, people in charities, like yourself, for instance. So I'm always very open to have open like interviews, to give talks, to give seminars, to reply to questions from patients and from families, from the scientific perspective, of course, because I'm not a doctor. I'm not, as I said before, involved in clinical care. So there is, there isn't much I can really contribute to in that field, but what I can do is to really reasssure patients that we are trying our best to try to find new treatments and to help them understand what we what we're doing, and where we think this can be potentially leading to new therapeutic approaches for them. But also, I think it's important to make them understand that these things take time. So because sometimes when you have this kind of research findings, you see in the media, for example, that they're frequently exaggerated, so they present them as if you have already found a cure against the disease. And I think that's extremely dangerous. So something that I also try to do when I participate in these dissemination activities is to be very realistic about what we do. So it's like, this is research. We are now in the preclinical stage. We have these results which are extremely promising, I believe, and which can potentially lead to new treatments, but it's important to understand that this may take another 5 to 10, 15 years in the best case scenario. Best case scenario. Sorry, and it's it's also important to understand that many times the results that we have in preclinical models do not translate to patients. So my involvement has been mostly in terms of, yeah, dissemination and making sure that our work is reaching the lay public,

Chandos: 12:55

and if people do have any questions of how they can get involved or they want to learn more about the research that you're doing, how can they find out about you and the team behind the research

Unknown: 13:07

so they can reach out. So there is the Joyce lab web page, there is contact information there. I'm always happy to take and reply to emails. I'm also reachable by my Twitter and in LinkedIn. And we're also organising with the charity now some activities, for example, a Q A session which should be published soon, in which ideas that people can post their questions and I will try to answer them. And sometimes we also organize meetup sessions with with patients and people who are interested with exactly the same idea, to just give them the opportunity to ask whatever they are curious about, and for us to also try to provide them with answers. But again, from a scientist perspective, not from a medical doctor perspective,

Chandos: 13:53

and it's given that idea that, yes, we are working towards a solution or a way of working differently, but it's going to take time, and I think that's so important, because I know that from my perspective of having a brain tumour like you can often be told things about your treatment and expect it's going to just make everything better, and it's that doesn't necessarily it helps you along the way a little bit, and makes you feel better and stuff. And I guess when looking at glioblastomas and impact they have on the quality of life and stuff. It's the research that you're doing is so vital. So firstly, thank you. On behalf of myself and everyone listening, and it's been amazing to chat to you.

Unknown: 14:37

Thank you. Yeah, it's, it's, of course, not only meets many, many people all over the world working on this, but I think it's, it's really something important and something necessary, and another big problem that we need to tackle, which unfortunately affects not only in this case, glioblastoma patients, but many other cancer patients which nowadays don't have a cure. So all I can say is that, from our side, we are doing our best. We're working hard, and we are trying to push as much as possible to move on with the research and to get results that will be someday, hopefully translatable into a tangible benefit for for patients.

Chandos: 15:13

Thank you. Thanks again for listening to this episode of The Brain Tumor Charity podcast. Whether you've been diagnosed the brain tumor or a family member or friend has the charity are here to help. Call 0808 800 0004, That's 0808 800 0004 or visit thebraintumourcharity.org for more information.

Sarah: 15:36

If you've enjoyed this episode, it would really help us if you could head on over to Apple podcast Spotify, or wherever you get your podcast, and leave us a review, as it really helps podcasts like this to reach more people. Thank you. You.