PDX imaging models in brain tumours

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Published: 11 May 2018
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Prof Kevin Brindle - Cancer Research UK Cambridge Institute, Cambridge, UK

Prof Brindle talks to ecancer at the Cancer Research UK Brain Tumour Conference 2018 in London about the use of PDX imaging models in brain tumours.

He discusses a new metabolic imaging technique that improves sensitivity of magnetic resonance.

He goes on to talk about pharmacokinetics and pharmacodynamics and how the new imaging technique can tell if drugs have crossed the blood-brain barrier and reached the target site or not.

I work in imaging, mainly magnetic resonance imaging, and we’ve been working for some time now, maybe the last 20-25 years, on developing imaging methods to detect very early evidence of treatment response so that you could use that then to guide treatment. Obviously I’m here, I’m going to talk about imaging brain tumours, mainly PDX models of brain tumours. We’ve been developing a new technique, a new metabolic imaging technique with MR that massively increases sensitivity and allows us to interrogate the metabolism of the tumour essentially in real time. We can use that method to detect very early evidence of treatment results – we see very early changes in metabolic activity post-treatment.

How does this new technique work?

It’s a way of massively increasing the sensitivity of magnetic resonance. Magnetic resonance is an intrinsically insensitive technique because you’re looking at very weak interaction between the nuclear spin and the magnetic field. This technique works by you can imagine that some atomic nuclei behave like small bar magnets and some of them line up with the field but some of them actually, because it’s such a weak interaction, line up against the field. But it’s that population difference, you have slightly more spins aligned with the field, and it’s that population difference which gives rise to signal. So the physics of this goes back to the 1950s, in fact, but a group working in Malmö in Sweden back in the 1990s developed a way… As I said, it had been worked on for many years but they made a practical way of polarising the spins and making them all line up and you do this at very, very low temperature. But they developed a way of rapidly warming the sample back up to room temperature and retain that spin polarisation. So transiently you have this massive gain in sensitivity.
You then take this material that you’ve polarised the spins and inject it intravenously, and this has been done in patients now, and for a few minutes you have a huge amount of signal so you can track where this labelled molecule goes in the body. But more importantly, you can see its metabolic interconversion with other metabolites. So it’s sort of real-time biochemistry - you can watch in real time how this molecule is taken up by a tumour cell and subsequently metabolised.
That process we know changes. Some drugs have a very direct metabolic effect so you see almost instantly a change in the way that they behave. I say instantly, 12-24 hours, 48 hours, it takes a while but you nevertheless see these changes.

How is this impacting brain cancer treatment?

In fact the discussion was this morning about pharmacokinetics and pharmacodynamics. Essentially what we can tell you in some instances with some drugs that the drug actually has engaged with its target, it’s hit the target. You know that from this imaging experiment. So, for example, people were talking about labelling drugs and looking at drug transport, well that may or may not tell you whether it has actually got into the cell, for example, but a pharmacodynamic readout tells you the drug crossed the blood-brain barrier, it’s gone into the cell and it’s hit its target as well. So we see this as a way of image-treat-image-treat paradigm where as more and more drugs become available, and drugs targeted at particular types of treatment, we know that not everybody responds in the same way. When you’ve got a whole family of drugs or a spectrum of drugs that you can use, or you might want to use drug combinations as well, so if you can image very quickly whether the drug has worked or not then that’s of benefit. Clearly if a drug isn’t working you can switch to an alternative drug or an alternative protocol or administration protocol, for example.

I see it as complementary to other methods that already… So, for example, something there’s a lot of discussion about – you have sequencing and you can choose drugs on the basis of known mutations in the particular tumour, of course that’s very valuable and you can choose the drug up front, but we think you could then follow-up with imaging to see whether the drug is indeed working or not.

There are over twenty instruments now been sold worldwide and in the UK there are four sites now, four or five sites, that have got the instrumentation. Some activity in cardiac but mainly in oncology. So it’s still at a very early stage of development, a sort of proof of concept – we know it will work in patients, it has gone into the clinic but now we really need to understand can we do something useful with this, is it really going to change clinical practice? Clearly that’s what it needs to do to get more wider adoption. I think we’re at that stage where we’ve shown in principle it works and we can get a signal and we see changes in the signal. The next stage is in wider clinical studies can we use this now in a very productive way clinically.

Is there need for international collaboration?

Yes, particularly, as you might imagine, the US but there are also sites in Europe as well which are working with this technology. Although it’s now fifteen years since the first practical demonstration of the technique it took about another ten years to get it first into clinic. Now the hard work is really going to begin because we need… and of course at this stage it’s quite expensive to do these studies as well, but we need to look at lots more patients and different diseases as well. On the basis of preclinical data we think we know where it might work but we need to demonstrate that now in patients.
It’s still watch this space. We’re very excited by it, to actually see it go into the clinic for the first time but we also recognise it’s going to take a while before we really understand what we can do with it.