Passage of treatments at the blood-brain barrier

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Published: 11 May 2018
Views: 1518
Prof William Elmquist - University of Minnesota, Minneapolis, USA

Prof Elmquist speaks with ecancer at Cancer Research UK Brain Tumour Conference 2018 in London about the effect of drug permeability at the blood-brain barrier on treatment prospects.

He describes potential strategies to improve drug delivery, such as inhibiting transporter proteins and utilising nanoparticles, and outlines his work with patient derived xenografts and new imaging techniques to assess treatment efficacy.

I’m talking about how the blood-brain barrier can be involved in limiting drug distribution to the tumour and in particular to the growing edge or the invasive part of a brain tumour, likely GBM. The blood-brain barrier is comprised of a variety of cell types in your brain capillaries and it keeps drugs from transporting from the blood into the brain parenchyma or from the blood into the tumour site in some areas. The tumour is highly heterogeneous in terms of its blood-brain barrier – some areas can get drugs, some areas do not. It’s those areas that do not get drugs that we’re really concerned about, obviously, because then even an effective drug will not kill the tumour.

One way of getting around it is going to be developing new drugs that have better blood-brain barrier permeability from the onset. So, for instance, we saw this morning in our keynote speaker had a beautiful drug, talked about all the mechanistic issues and how they really figured out the biochemistry involved. However, as a caveat he said, ‘And, of course, it doesn’t cross the blood-brain barrier. You can’t have everything in life.’ Well, we’d like to have most things in life so we can preserve life and in the case of getting an active drug across the blood-brain barrier that’s important. So I would say from a chemical synthesis standpoint we need to do a better job of taking that particular attribute into consideration.
Other ways of doing it, we know mechanisms that limit drug delivery across the BBB, or blood-brain barrier, and those include transporters like efflux transport proteins. We can make sure that our drugs either are not substrates for these efflux transporters or we do something to overcome it like an inhibitor of the transporter itself. These would be strategies. Other strategies include nanoparticle or liposomal delivery mechanisms or shuttles across an intact blood-brain barrier. These are fraught with a variety of issues, the foibles include things like payload, how much drug you can actually get across using these methods. In my estimation where greatest impact will be felt will be in the design of the molecule itself.
We’re working on both GBM, glioblastoma, and brain mets from things like lung and melanoma cells. We’re working on trying to do essentially the pharmacokinetic/pharmacodynamic relationships in a variety of PDXs or patient-derived xenografts that recapitulate the tumour maybe in a more realistic way than many other models. Trying to do screens of various compounds and even within a series of compounds look at those structures that would have the greatest possibility of activity because they have the greatest penetration across the BBB. This includes both delivery and potency. So if you have something that’s potent enough you don’t need to get much in but if it’s not that potent you need to get more in. So it’s a simple equation but hard to solve.

Is this something that will be reported in upcoming trials?

We’re undergoing a phase 0 trial right now at Mayo Clinic in Rochester, Minnesota, where, guided by various imaging techniques, particularly MRI, we’re on initial resection of GBM, we’re looking at different regions of the MRI and seeing how much drug penetrates in these different regions. That will give us some idea about choice of drug. We have two issues at hand, one is delivery and the other is the genetics of the tumour itself. So we need to improve delivery towards the right target and that should make a difference.

In this phase 0 trial we’re actually measuring two compounds that are given to everybody who gets a craniotomy: an antibiotic which should not get across an intact BBB very well and an anti-epileptic which does. So these are given as prophylactic therapy when you have a resection or any craniotomy. So basically we have a good pair of, in essence, biomarker compounds to determine what’s going on with the BBB in that region which is guided by MRI. So that will give us a lot of information for future trials.

What are the key messages?

One key message is that delivery makes a difference. It’s often important to recognise that if we don’t know what to do about something then we just kind of say, ‘Well, that’s life.’ Well, it’s important and so we have to take it into consideration. We do all the mechanistic studies and all this other stuff but something so simple which may be as boring as the delivery of the compound to the cell of interest needs to be taken into consideration.
We need to change our paradigm in how we do not only our clinical trials but our preclinical trials. And that paradigm should include right up front a consideration of the delivery of the compound to the cell of interest. So that continues to be my key point and I will continue to make that key point until we start doing that.