The pioneering scan that could tell Cambridge cancer patients if treatment is working within days

The Cambridge Independent is campaigning to raise £100,000 with Cancer Research UK to pay for trials at Addenbrooke'.

It’s a revolutionary technique, many years in the making, and it could have a huge impact on how cancer patients are treated in future.

The Cambridge Independent has launched a campaign with Cancer Research UK (CRUK) to raise £100,000 to help fund clinical trials at Addenbrooke’s.

The trials will assess whether rapid scanning technology can help guide oncologists in assessing the effectiveness of cancer treatments in patients.

The project is jointly led by Professor Kevin Brindle of the CRUK Cambridge Institute, and Dr Ferdia Gallagher, from the Department of Radiology at Cambridge.

Currently, doctors determine whether a treatment is working for patients by examining whether a tumour is shrinking or not using CT (computerised tomography) scans or MRI (magnetic resonance imaging).

“The problem with that approach is that it can take quite a long time before you see any tumour shrinkage and it’s actually quite difficult to measure as well,” says Prof Brindle.

“Some treatments are cytostatic – they don’t necessarily cause the tumour to shrink but they stop it growing, so clearly assessing the response to those drugs is more difficult if you just use anatomical imaging.

“What we do and what has been done with other techniques is to look at tumour metabolism. Tumours use lots of glucose, for example, and they use this to grow by making biosynthetic intermediates that go in to making new proteins, membranes and so on.”

One imaging technique that has been around for some years that makes use of this high uptake of glucose by tumours is called positron emission tomography (PET).

“You use a radioactively-labelled glucose molecule and that is often avidly taken up by a tumour. It gets trapped inside a tumour cell so it lights up the tumour in the PET image,” said Prof Brindle. “It has been shown that you can see treatment response quite quickly with this technique, before there is any evidence of tumour shrinkage.

“The only potential drawback is that it uses ionising radiation – although not a lot. But I think a lot of oncologists would not want to do multiple PET exams to guide treatment in an individual, especially in a relatively young patient, for example.” Also this PET technique does not work so well in some tumours, such as prostate and brain tumours.

The technique Prof Brindle and Dr Gallagher have helped to develop over the last decade looks at metabolism in a different way using MRI.

“In conventional MRI you look at tissue water,” explains Prof Brindle. “It maps the distribution of water in the body and that gives you an anatomical image.

“It’s a little bit more complicated than that because the signal that the water molecule gives off in the MRI scan can vary depending on the composition of the tissue. It gives very good soft tissue contrast – unlike X-ray, for example.

“You can exploit that in many ways but it doesn’t give you any direct information about the metabolism of the tumour.

“We’ve known since the beginning of the development of MRI that you can see signals from small molecules inside the cell – metabolites, like glucose and the molecules produced from glucose.

“The problem is that these molecules are present at concentrations about 10,000 times lower than water so you can’t really image them except at very low resolution.

“Also, if you just took a snapshot of these molecules, there is no dynamic information.”

This means with a standard imaging approach a doctor couldn’t tell how quickly a tumour is taking up and using the material – data that is crucial in understanding whether a therapy is working.

“When a tumour starts to respond to treatment you see a change in how fast it metabolises molecules like glucose,” explains Prof Brindle.

“So the technology we’ve been using increases the sensitivity in the MRI experiment by more than 10,000 times – a massive gain.

“The underlying physical principles were known in the 1950s but it took another 50 years before a practical application in the clinic became possible.”

MRI applies a strong magnetic field that prompts protons in water molecules inside our bodies to line up – like bar magnets. About half go up and half go down, cancelling each other out, but a few per million are unmatched.

A radio frequency magnetic field is applied to the patient, causing these unmatched protons to produce a signal.

When the radio frequency magnetic field is turned off, the unmatched protons return to their normal position, emitting energy that can be imaged using a computer.

Since the human body has so much water in it, the signal is strong enough to detect. But this approach won’t work with metabolites.

“When you are looking at molecules at 10,000-fold lower concentrations than water, they are really hard to detect,” says Prof Brindle. “So the way this machine works is we take a molecule and put a carbon-13 label in it.”

This isotopic labelling is like putting a flag on a molecule so that its passage in the body can be followed.

Carbon-13, a non radioactive isotope of carbon, is used because the most commonly occurring isotope – carbon-12 – does not give off a MRI signal. However, carbon-13 doesn’t line up with a magnetic field very well at normal temperatures.

“We take the molecule down to minus 272 degrees Centigrade, a degree above absolute zero. At that low temperature, we can make all of these carbon-13 nuclei line up with the field and that gives us a massive gain in sensitivity,” says Prof Brindle.

“The problem is it’s at minus 272 degrees but the key innovation, introduced back in the late 1990s, is that you can warm the sample up extremely quickly and these nuclei stay lined up with the field. You then inject that material into the patient.

“As you start warming it up, the nuclei start to relax back to their normal equilibrium and you lose signal. But it lasts for a few minutes. So when we inject it into the patient, we have enough signal to image it and where it is in the body.”

The key innovation is that this approach enables the team to see when the molecule being studied is converted by the tumour and the speed at which that happens.

“When we treat a tumour, we inject a labelled molecule called pyruvate and it’s taken up by the tumour and converted into lactate. The rate at which that happens tells us something about how healthy that cell is,” says Prof Brindle.

“In a tumour cell growing rapidly, that reaction is very fast. If we successfully treat with a drug, that almost invariably decreases the rate at which that happens and we can image that.”

The process is similar to what happens when we exercise. Muscles take up glucose very quickly to fuel muscle contraction, converting it to pyruvate. But it can happen so quickly that there is not time to oxidise the pyruvate, so it is dumped as lactate. Too much of it causes cramp.

Tumours use this glycolytic pathway to make energy but also to make intermediates that are needed to build things like proteins and lipids.

“The idea that we’re pursuing is that some drugs, if they are effective, will decrease this exchange within 48-72 hours – maybe even less in some cases. It means we can tell very quickly whether a drug is effective or not,” says Prof Brindle.

“In oncology, 20 or 30 years ago, most patients got treated with the same very toxic drugs. Now we have much more targeted drugs that hit very specific targets in the tumour cells.

“Not all patients’ tumours are the same – they can vary substantially. A drug can be very effective in one patient and completely ineffective in another.

“What you want to do is target therapy more effectively and one way to do that is to image it straight after treatment and find if the drug hit its target. Is there any evidence it is doing something in this patient?”

It is hoped that once a consultant oncologist analyses the data, he or she can then alter a patient’s treatment immediately if necessary.

“This is really in its infancy,” says Prof Brindle. “We’ve only run a few patients. But we have a lot of pre-clinical model data that shows very clearly that you see inhibition of this reaction and we are planning to do our first treatment study in the near future.”

“The key question is what is the clinical value of this? Can we use this to guide treatment? For that, we need to do multi-centre studies in lots of patients to gather the evidence that this is an effective way to guide treatments.”

The technique could suit a wide range of cancer treatments but initial clinical studies at Addenbrooke’s will focus on patients with breast and brain cancer. It is hoped 20-30 patients can be recruited to demonstrate the technique’s potential.

The hope is that by identifying patients whose tumours are resistant to treatment this will enable an alternative combination of drugs to be administered.

Prof Brindle is urging companies to get involved and help the fundraising campaign – and said the interaction between researchers and private companies is critical in progressing therapies.

“We’ve been focused on taking basic science into the clinic and we can only do that if a company is prepared to run with it.

“All through my career I’ve had interactions with pharma and imaging companies. To translate you need that interaction,” he said.

For more information on how to get involved and how your business will benefit, email laura.holland@cancer.org.uk. To support the trial visit justgiving.com/fundraising/cambridgeresearchproject.

A decade in the making

The technology was originally developed by Buckinghamshire biotech firm Amersham, which was bought by GE Healthcare. It continued the project and in 2006 put prototype machines in three labs – one in Prof Brindle’s, another in Oxford and a third at UCFF, the University of California in San Francisco.

“We started in 2006 and published our first paper in 2007,” said Prof Brindle. “Over the next few years, we built up an evidence base in pre-clinical models that this was a valuable technique.

“The very first clinical study was published in 2013 at UCFF. GE Healthcare then built a clinical device and over 20 of these have now been sold. They placed machines initially in Oxford, Cambridge, UCFF, Copenhagen, New York and Toronto and they all now use it and have done studies.”

Prof Brindle and Dr Gallagher are working with co-investigators and collaborators at the University of Cambridge and at Addenbrooke’s Hospital including Professor David Lomas (radiology), Professor Ian Wilkinson (Department of Medicine), Dr Bristi Basu (oncology) and Anita Chhabra (pharmacy).

The facility and clinical trials are funded and supported by the Wellcome Trust, Cancer Research UK, Addenbrooke’s Charitable Trust, the Cambridge Cancer Centre, Cambridge University Hospitals NHS Foundation Trust, GE Healthcare and the University of Cambridge. The research is also funded by the Wellcome Trust strategic award.