Overcoming the blood-brain barrier to treat glioblastoma

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Published: 11 May 2018
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Prof Elga De Vries - VU University Medical Center, Amsterdam, The Netherlands

Prof De Vries talks to ecancer at the Cancer Research UK Brain Tumour Conference 2018 in London about the difficulty of passing drugs across the blood-brain barrier (BBB).

Two possible developments are discussed; packaging drugs in liposomes, and bursting micro-bubbles on to specific areas of the BBB to release the barrier using ultrasound.

Johanna Joyce invited me to talk on the blood-brain barrier and also how to overcome the blood-brain barrier as that is a problem in the treatment of GBMs, glioma. So what I will talk about tomorrow is also give a little bit more of an overview of the function of the blood-brain barrier, what are the difficulties to overcome it during treatment and also discuss a number of the novel developments in the field.

You have the endothelial cells that line the vessels in the brain; they are quite specialised so they have tight junction molecules and they have also efflux pumps. They thereby maintain all the potential neurotoxic stuff within circulation, however, that is also a problem when you want to treat diseases that occur behind the blood-brain barrier. Especially also in glioblastoma a number of the tumours have a leaky vasculature but the more low-grade still have an intact blood-brain tumour barrier and they are equipped to keep all the anti-cancer drugs out. So I will be discussing how the barrier is regulated and also strategies to overcome it.

There are a couple of strategies and some have worked and some have not. I will highlight two recent developments that are the most important. One is the generation of liposomes in which you can encapsulate anti-cancer drugs like doxorubicin. You can have a molecule on the outside of the liposome that will recognise a molecule on the endothelial cells and then by this recognition it will be sort of taken up and transported across the blood-brain barrier. They have been quite successful in animal models and they are now moving into clinical phase II already with these liposomal formulations. In this sense you have a higher anti-cancer drug within the tumour and you also lower the systemic concentration so thereby you have less side effects. So that is one thing.

The other thing, so-called microbubbles - you can inject those and then with the use of ultrasound these microbubbles will start resonating and they will burst, it sound a little bit… Then you have a local opening of the vasculature and then you can at the site where you have your ultrasound activated microbubbles you get a delivery of the drug into the tumour. This is especially for more diffuse tumours, it might be the way to go. You can also use MR guiding to really localise your ultrasound, the location of your ultrasound and your microbubbles. So it’s technically quite challenging but I think that is also very interesting. They are working now towards initial clinical trials with this so hopefully that works as well.

And other things there, so you can inhibit these efflux pumps, like I describe d earlier, so you can inhibit them and then give a drug. You can also open a blood-brain barrier and then give the drug but it’s all really harsh measures, so to speak. Also you will affect healthy tissue and that is the biggest problem – how do you get your drug at the site where you really want it to be? In the necrotic areas you of course will have leaky blood vessels, like I also discussed this morning. So then it’s not a problem but you want to fight the more diffuse tumour cells actually.

Are these the novel treatments of the future?

The liposomal is really entering now the clinical stages and the focussed ultrasound in combination with the microbubbles, I think it’s promising. It will be clinically challenging because you need to have the ultrasound machine but I think a lot of people are looking into this now.  I know people in Sunnybrook are working on this and also within the Netherlands there is now a joint effort to work on glioblastoma with this new cancer centre being set up in Utrecht at our university there. They will also look into these types of strategies to treat patients. But still in models it works nicely but we now need to take the step to the patient.

Can there be any damage associated with these treatments?

If the microbubbles are there then that is what you affect, actually. That is one of the things that is not known - so if you do this frequently what is actually the damage. People have not really looked into this. They looked into models but then they only looked for a couple of hours or maybe a couple of days but, again, only experimental models. For humans we do not actually know how dangerous this is, whether it’s dangerous. But, then again, if you have a glioma I think you need to try everything even if there is some tissue damage, that you need to fight it.

What are the key messages?

Consider the blood-brain barrier if you’re treating a patient. I think it has been ignored and that is also the reason that a number of the trials have failed. Again, you can treat the leaky vasculature and it will work fine but if you’re really looking into ways to treat the diffuse nature of the tumour really look into the blood brain barrier and also consider it in your treatment strategies. Either open it or use this ultrasound or find other technical ways to circumvent it but keep it in mind. Because it is not ignored but people may forget a little bit on it. What we need to look into is how this blood-brain tumour barrier in the more low grade tumours is regulated and can we use that to find ways to maybe have new drug delivery transporters to identify them, but still that’s a long way to go. But we need to look into that.