̽��ֱ�� of Cambridge - Kevin Brindle

Imaging technique allows rapid assessment of ovarian cancer subtypes and their response to treatment

jg533 — Fri, 06 Dec 2024 09:17:27 +0000

̽��ֱ��technique, called hyperpolarised carbon-13 imaging, can increase the detected signal in an MRI scanner by more than 10,000 times. Scientists have found that the technique can distinguish between 2 different subtypes of ovarian cancer, to reveal their sensitivities to treatment.

They used it to look at patient-derived cell models that closely mimic the behaviour of human high grade serous ovarian cancer, the most common lethal form of the disease. ̽��ֱ��technique clearly shows whether a tumour is sensitive or resistant to Carboplatin, one of the standard first-line chemotherapy treatments for ovarian cancer.

This will enable oncologists to predict how well a patient will respond to treatment, and to see how well the treatment is working within the first 48 hours.

Different forms of ovarian cancer respond differently to drug treatments. With current tests, patients typically wait for weeks or months to find out whether their cancer is responding to treatment. ̽��ֱ��rapid feedback provided by this new technique will help oncologists to adjust and personalise treatment for each patient within days.

̽��ֱ��study compared the hyperpolarised imaging technique with results from Positron Emission Tomography (PET) scans, which are already widely used in clinical practice. ̽��ֱ��results shows that PET did not pick up the metabolic differences between different tumour subtypes, so could not predict the type of tumour present.

̽��ֱ��report is published today in the journal Oncogene.

“This technique tells us how aggressive an ovarian cancer tumour is, and could allow doctors to assess multiple tumours in a patient to give a more holistic assessment of disease prognosis so the most appropriate treatment can be selected,” said Professor Kevin Brindle in the ̽��ֱ�� of Cambridge’s Department of Biochemistry, senior author of the report.

Ovarian cancer patients often have multiple tumours spread throughout their abdomen. It isn’t possible to take biopsies of all of them, and they may be of different subtypes that respond differently to treatment. MRI is non-invasive, and the hyperpolarised imaging technique will allow oncologists to look at all the tumours at once.

Brindle added: “We can image a tumour pre-treatment to predict how likely it is to respond, and then we can image again immediately after treatment to confirm whether it has indeed responded. This will help doctors to select the most appropriate treatment for each patient and adjust this as necessary.

“One of the questions cancer patients ask most often is whether their treatment is working. If doctors can speed their patients onto the best treatment, then it’s clearly of benefit.”

̽��ֱ��next step is to trial the technique in ovarian cancer patients, which the scientists anticipate within the next few years.

Hyperpolarised carbon-13 imaging uses an injectable solution containing a ‘labelled’ form of the naturally occurring molecule pyruvate. ̽��ֱ��pyruvate enters the cells of the body, and the scan shows the rate at which it is broken down - or metabolised – into a molecule called lactate. ̽��ֱ��rate of this metabolism reveals the tumour subtype and thus its sensitivity to treatment.

This study adds to the evidence for the value of the hyperpolarised carbon-13 imaging technique for wider clinical use.

Brindle, who also works at the Cancer Research UK Cambridge Institute, has been developing this imaging technique to investigate different cancers for the last two decades, including breast, prostate and glioblastoma - a common and aggressive type of brain tumour. Glioblastoma also shows different subtypes that vary in their metabolism, which can be imaged to predict their response to treatment. ̽��ֱ��first clinical study in Cambridge, which was published in 2020, was in breast cancer patients.

Each year about 7,500 women in the UK are diagnosed with ovarian cancer - around 5,000 of these will have the most aggressive form of the disease, called high-grade serous ovarian cancer (HGSOC).

̽��ֱ��cure rate for all forms of ovarian cancer is very low and currently only 43% of women in England survive five years beyond diagnosis. Symptoms can easily be missed, allowing the disease to spread before a woman is diagnosed - and this makes imaging and treatment challenging.

̽��ֱ��research was funded by Cancer Research UK.

Reference: Chia, M L: ‘Metabolic imaging distinguishes ovarian cancer subtypes and detects their early and variable responses to treatment.’ Oncogene, December 2024. DOI: 10.1038/s41388-024-03231-w

An MRI-based imaging technique developed at the ̽��ֱ�� of Cambridge predicts the response of ovarian cancer tumours to treatment, and rapidly reveals how well treatment is working, in patient-derived cell models.

We can image a tumour pre-treatment to predict how likely it is to respond, and then we can image again immediately after treatment to confirm whether it has indeed responded

Kevin Brindle

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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Imaging technique could replace tissue biopsies in assessing drug resistance in breast cancer patients

cjb250 — Tue, 06 Oct 2020 13:18:49 +0000

In a study published in the journal Cancer Cell, researchers at the Cancer Research UK (CRUK) Cambridge Institute have shown how a new technique known as hyperpolarisation – which involves effectively magnetising molecules in a strong magnetic field – can be used to monitor how effective cancer drugs are at slowing a tumour’s growth.

In healthy tissue, cell proliferation is a tightly controlled process. When this process goes wrong, cell proliferation can run away with itself, leading to unchecked growth and the development of tumours.

All tissue needs to be ‘fed’. As part of this process – known as metabolism – our cells break down glucose and other sugars to produce pyruvate, which is in turn converted into lactate. This is important for producing energy and the building blocks for making new cells.

Tumours have a different metabolism to healthy cells, and often produce more lactate. This metabolic pathway is affected by the presence of a protein known as FOXM1, which controls the production of a metabolic enzyme that converts pyruvate into lactate. FOXM1 also controls the production of many other proteins involved in cell growth and proliferation.

Around 70% of all cases of breast cancer are of a type known as estrogen-receptor (ER) positive. In many ER-positive breast cancer cases, an enzyme known as PI3Ka is activated. This leads to an abundance of FOXM1, enabling the cancer cells to grow uncontrollably – the characteristic sign of a tumour cell.

Drugs that inhibit PI3Ka are currently being tested in breast cancer patients. Such drugs should be able to decrease the amount of FOXM1 and check the tumour’s growth. However, a patient’s tumour may have an innate resistance to PI3Ka inhibitors, or can acquire resistance over time, making the drugs increasingly less effective.

Dr Susana Ros, first author from the CRUK Cambridge Institute, said: “Thanks to advances in cancer treatments, our medicines are becoming more and more targeted, but not all drugs will work in every case – some tumours are resistant to particular drugs. What we need are biomarkers – biological signatures – that tell us whether a drug is working or not.”

̽��ֱ��researchers took breast cancer cells from patients and grew them in mouse ‘avatars’ to allow them to study the tumours in detail. They found that in tumours resistant to PI3Ka inhibitors, cancer cells continue to produce FOXM1 – meaning that this molecule could be used as a biomarker for drug resistance in patients with ER-positive breast cancer.

Checking whether a tumour is continuing to produce FOXM1 – and hence whether the PI3Ka inhibitor is still working – would usually involve an invasive tissue biopsy. However, researchers have used a new imaging technique to monitor this in real time and non-invasively.

̽��ֱ��technique developed and used by the team is known as hyperpolarisation. First, the team produces a form of pyruvate whose carbon atoms are slightly heavier than normal carbon atoms (they carry an additional neutron and are hence known as carbon-13 molecules). ̽��ֱ��researchers then ‘hyperpolarise’ – or magnetise – the carbon-13 pyruvate by cooling it to around one degree above absolute zero (-272°C) and exposing it to extremely strong magnetic fields and microwave radiation. ̽��ֱ��frozen material is then thawed and dissolved into an injectable solution.

Patients are injected with the solution and then receive a regular MRI scan. ̽��ֱ��signal strength from the hyperpolarised carbon-13 pyruvate molecules is 10,000 times stronger than that from normal pyruvate, making the molecules visible on the scan. ̽��ֱ��researchers can use the scan to see how fast pyruvate is being converted into lactate – only the continued presence of FOXM1 would allow this to happen, and this would be a sign that the drugs are not working properly.

Image: False colour image of a breast tumour (outlined) pre- and post-treatment with a PI3Ka inhibitor. Weaker colours post-treatment indicate that the drug is working. (Credit: Brindle Lab)

Dr Ros added: “We’ve been able to detect the presence of FOXM1, our biomarker, by using this new imaging technique in breast cancer models to look for a proxy – that is, how quickly pyruvate is converted to lactate.”

Professor Kevin Brindle, senior author of the study, commented: “In the future, this could provide us with a rapid assessment of how a breast cancer patient is responding to treatment without the need for invasive biopsies. This information could help put an end to giving treatments that are not working and the side effects that accompany them. Currently, patients can wait a long time to find out if a treatment is working. This technique could shorten this time, and help to tailor treatment for individual patients.”

Reference
Ros, S et al. Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER+ Breast Cancer. Cancer Cell; 24 Sept 2020; DOI: 10.1016/j.ccell.2020.08.016

Imaging techniques could replace the need for invasive tissue biopsies in helping rapidly determine whether cancer treatments are working effectively, according to researchers at the ̽��ֱ�� of Cambridge.

Currently, patients can wait a long time to find out if a treatment is working. This technique could shorten this time, and help to tailor treatment for individual patients

Kevin Brindle

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Husband supporting a sick wife

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

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̽��ֱ��Royal Society announces election of new Fellows 2020

jg533 — Wed, 29 Apr 2020 17:53:50 +0000

Fellows are chosen for their outstanding contributions to scientific understanding. ̽��ֱ��62 newly elected Fellows embody the global nature of science, and are elected for life through a peer review process based on excellence in science. Past Fellows and Foreign Members include Isaac Newton, Charles Darwin, Dorothy Hodgkin and Stephen Hawking.

̽��ֱ��Royal Society is a self-governing Fellowship made up of the most eminent scientists, engineers and technologists from the UK and the Commonwealth. Its Foreign Members are drawn from the rest of the world. ̽��ֱ��Society’s fundamental purpose is to recognise, promote and support excellence in science and to encourage the development and use of science for the benefit of humanity.

Sir Venki Ramakrishnan, President of the Royal Society, said: “At this time of global crisis, the importance of scientific thinking, and the medicines, technologies and insights it delivers, has never been clearer. Our Fellows and Foreign Members are central to the mission of the Royal Society, to use science for the benefit of humanity.

"While election to the Fellowship is a recognition of exceptional individual contributions to the sciences, it is also a network of expertise that can be drawn on to address issues of societal, and global significance. This year’s Fellows and Foreign Members have helped shape the 21st century through their work at the cutting-edge of fields from human genomics, to climate science and machine learning.

"It gives me great pleasure to celebrate these achievements, and those yet to come, and welcome them into the ranks of the Royal Society.”

̽��ֱ��Cambridge scientists announced today as Royal Society Fellows are:

Professor Kevin Brindle FMedSci, Department of Biochemistry and Cancer Research UK Cambridge Institute. His current research is focused on novel imaging methods for detecting cancer progression and to monitor early tumour responses to treatment, with an emphasis on translating these techniques to the clinic.

Professor Vikram Deshpande, Department of Engineering, for his seminal contributions in microstructural mechanics. His works include developing ‘metallic wood’, sheets of nickel as strong as titanium, but four-times lighter thanks to their plant-like nanoscale pores.

Professor Marian Holness, Department of Earth Sciences. She has created a new approach to decoding rock history, and concentrates on understanding the evolution of bodies of magma trapped in the crust, which ultimately controls the eruptive behaviour of any overlying volcano.

Professor Giles Oldroyd, Russell R Geiger Professor of Crop Science, Crop Science Centre and Group Leader, Sainsbury Laboratory. He is leading an international research programme attempting to achieve more equitable and sustainable agriculture through the enhanced use of beneficial microbial associations.

Professor Hugh Osborn, Department of Applied Mathematics and Theoretical Physics for work in theoretical physics on quantum field theory and in particular conformal field theory.

Professor Didier Queloz, Cavendish Laboratory, for his part in the discovery of the first planet beyond our solar system, for which he shared the Nobel Prize in Physics last year. Hundreds more exoplanets have since been revealed by his pioneering observational techniques.

Dr Sarah Teichmann FMedSci, Director of Research, Cavendish Laboratory and Senior Research Fellow, Churchill College, for her contributions to computational biology and genomics, including her role in founding and leading the Human Cell Atlas international consortium to map all cell types in the human body.

Professor Stephen Young, Department of Engineering, for pioneering the statistical approach to language processing - namely, treating conversation as a reinforcement learning problem - that made the speech-recognition products in millions of homes a reality.

Professor Jack Thorne, Department of Pure Maths and Mathematical Statistics for multiple breakthroughs in diverse areas of algebraic number theory. At age 32, he becomes the youngest living member of the Fellowship.

In addition, Dr William Schafer at the MRC Laboratory of Molecular Biology, based at the Cambridge Biomedical Campus, has been elected as a Fellow.

Nine Cambridge scientists are among the new Fellows announced today by the Royal Society.

At this time of global crisis, the importance of scientific thinking, and the medicines, technologies and insights it delivers, has never been clearer.

Venki Ramakrishnan

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Magnetised molecules used to monitor breast cancer

Anonymous — Wed, 22 Jan 2020 09:07:12 +0000

This is the first time researchers have demonstrated that this scanning technique, called carbon-13 hyperpolarised imaging, can be used to monitor breast cancer.

̽��ֱ��team based at the Cancer Research UK Cambridge Institute and the Department of Radiology, ̽��ֱ�� of Cambridge, tested the technique in seven patients with various types and grades of breast cancer before they had received any treatment.

They used the scan to measure how fast the patients’ tumours were metabolising a naturally occurring molecule called pyruvate, and were able to detect differences in the size, type and grade of tumours – a measure of how fast growing, or aggressive the cancer is.

̽��ֱ��scan also revealed in more detail the ‘topography’ of the tumour, detecting variations in metabolism between different regions of the same tumour.

Professor Kevin Brindle, lead researcher from the institute, said: “This is one of the most detailed pictures of the metabolism of a patient’s breast cancer that we’ve ever been able to achieve. It’s like we can see the tumour ‘breathing’.

“Combining this with advances in genetic testing, this scan could in the future allow doctors to better tailor treatments to each individual, and detect whether patients are responding to treatments, like chemotherapy, earlier than is currently possible”.

Hyperpolarised carbon-13 pyruvate is an isotope-labelled form of the molecule that is slightly heavier than the naturally occurring pyruvate which is formed in our bodies from the breakdown of glucose and other sugars.

In the study, the scientists ‘hyperpolarised’, or magnetised, carbon-13 pyruvate by cooling it to about one degree above absolute zero (-272°C) and exposing it to extremely strong magnetic fields and microwave radiation. ̽��ֱ��frozen material was then thawed and dissolved into an injectable solution.

Patients were injected with the solution and then received an MRI scan at Addenbrookes Hospital. Magnetising the carbon-13 pyruvate molecules increases the signal strength by 10,000 times so that they are visible on the scan.

̽��ֱ��researchers used the scan to measure how fast pyruvate was being converted into a substance called lactate.

Our cells convert pyruvate into lactate as part of the metabolic processes that produce energy and the building blocks for making new cells. Tumours have a different metabolism to healthy cells, and so produce lactate more quickly. This rate also varies between tumours, and between different regions of the same tumour.

̽��ֱ��researchers showed that monitoring this conversion in real-time could be used to infer the type and aggressiveness of the breast cancer.

̽��ֱ��team now hopes to trial this scan in larger groups of patients, to see if it can be reliably used to inform treatment decisions in hospitals.

Breast cancer is the most common type of cancer in the UK, with around 55,000 new cases each year. 80% of people with breast cancer survive for 10 years or more, however for some subtypes, survival is much lower.

Professor Charles Swanton, Cancer Research UK’s chief clinician, said: “This exciting advance in scanning technology could provide new information about the metabolic status of each patient’s tumour upon diagnosis, which could help doctors to identify the best course of treatment.

“And the simple, non-invasive scan could be repeated periodically during treatment, providing an indication of whether the treatment is working. Ultimately, the hope is that scans like this could help doctors decide to switch to a more intensive treatment if needed, or even reduce the treatment dose, sparing people unnecessary side effects.”

̽��ֱ��research was supported by Cancer Research UK Cambridge Institute and ̽��ֱ��Mark Foundation for Cancer Research.

Reference
Gallagher, FA et al. Imaging breast cancer using hyperpolarized carbon-13 MRI. PNAS; 21 Jan 2020; DOI: 10.1073/pnas.1913841117

A new type of scan that involves magnetising molecules allows doctors to see in real-time which regions of a breast tumour are active, according to research at the ̽��ֱ�� of Cambridge and published in Proceedings of the National Academy of Sciences.

This is one of the most detailed pictures of the metabolism of a patient’s breast cancer that we’ve ever been able to achieve. It’s like we can see the tumour ‘breathing’

Kevin Brindle

Left: Anatomic MR image of breast tumour; Right: Overlays of hyperpolarised 13C-MRI on anatomic images showing pyruvate and lactate in breast cancer

Yes

Cambridge extends world leading role for medical imaging with powerful new brain and body scanners

cjb250 — Mon, 24 Oct 2016 07:22:25 +0000

̽��ֱ��equipment, funded by the Medical Research Council (MRC), Wellcome Trust and Cancer Research UK, sits within the newly-refurbished Wolfson Brain Imaging Centre (WBIC), which today celebrates two decades at the forefront of medical imaging.

At the heart of the refurbishment are three cutting-edge scanners, of which only a very small handful exist at institutions outside Cambridge – and no institution other than the ̽��ֱ�� of Cambridge has all three. These are:

a Siemens 7T Terra Magnetic Resonance Imaging (MRI) scanner, which will allow researchers to see detail in the brain as tiny as a grain of sand
a GE Healthcare PET/MR scanner that will enable researchers to collect critical data to help understand how cancers grow, spread and respond to treatment, and how dementia progresses
a GE Healthcare hyperpolarizer that enables researchers to study real-time metabolism of cancers and other body tissues, including whether a cancer therapy is effective or not

These scanners, together with refurbished PRISMA and Skyra 3T MRI scanners at the WBIC and at the Medical Research Council Cognition and Brain Sciences Unit, will make the Cambridge Biomedical Campus the best-equipped medical imaging centre in Europe.

Professor Ed Bullmore, Co-Chair of Cambridge Neuroscience and Scientific Director of the WBIC, says: “This is an exciting day for us as these new scanners will hopefully provide answers to questions that we have been asking for some time, as well as opening up new areas for us to explore in neuroscience, mental health research and cancer medicine.

“By bringing together these scanners, the research expertise in Cambridge, and the latest in ‘big data’ informatics, we will be able to do sophisticated analyses that could revolutionise our understanding of the brain – and how mental health disorders and dementias arise – as well of cancers and how we treat them. This will be a powerful research tool and represents a big step in the direction of personalised treatments.”

Dr Rob Buckle, Director of Science Programmes at the MRC, adds: “ ̽��ֱ��MRC is proud to sponsor this exciting suite of new technologies at the ̽��ֱ�� of Cambridge. They will play an important role in advancing our strategy in stratified medicine, ultimately ensuring that the right patient gets the right treatment at the right time.”

Slide show: Click on images to expand

7T Medical Resonance Imaging (MRI) scanner

̽��ֱ��Siemens 7T Terra scanner – which refers to the ultrahigh strength of its magnetic field at 7 Tesla – will allow researchers to study at unprecedented levels of detail the workings of the brain and how it encodes information such as individual memories. Current 3T MRI scanners can image structures 2-3mm in size, whereas the new scanner has a resolution of just 0.5mm, the size of a coarse grain of sand.

“Often, the early stages of diseases of the brain, such as Alzheimer’s and Parkinson’s, occur in very small structures – until now too small for us to see,” explains Professor James Rowe, who will be leading research using the new 7T scanner. “ ̽��ֱ��early seeds of dementia for example, which are often sown in middle age, have until now been hidden to less powerful MRI scanners.”

̽��ֱ��scanner will also be able to pick up unique signatures of neurotransmitters in the brain, the chemicals that allow its cells to communicate with each other. Changes in the amount of these neurotransmitters affect how the brain functions and can underpin mental health disorders such as depression and schizophrenia.

“How a patient responds to a particular drug may depend on how much of a particular neurotransmitter present is currently present,” says Professor Rowe. “We will be looking at whether this new scanner can help provide this information and so help us tailor treatments to individual patients.”

̽��ֱ��scanner will begin operating at the start of December, with research projects lined up to look at dementias caused by changes to the brain almost undetectable by conventional scanners, and to look at how visual and sound information is converted to mental representations in the brain.

PET/MR scanner

̽��ֱ��new GE Healthcare PET/MR scanner brings together two existing technologies: positron emission tomography (PET), which enables researchers to visualise cellular activity and metabolism, and magnetic resonance (MR), which is used to image soft tissue for structural and functional details.

Purchased as part of the Dementias Platform UK, a network of imaging centres across the UK, the scanner will enable researchers to simultaneously collect information on physiological and disease-related processes in the body, reducing the need for patients to return for multiple scans. This will be particularly important for dementia patients.

Professor Fiona Gilbert, who will lead research on the PET/MR scanner, explains: “Dementia patients are often frail, which can present challenges when they need separate PET and MR scanners. So, not only will this new scanner provide us with valuable information to help improve understanding and diagnosis of dementia, it will also be much more patient-friendly.”

PET/MR will allow researchers to see early molecular changes in the brain, accurately map them onto structural brain images and follow their progression as disease develops or worsens. This could enable researchers to diagnose dementia before any symptoms have arisen and to understand which treatments may best halt or slow the disease.

As well as being used for dementia research, the scanner will also be applied to cancer research, says Professor Gilbert.

“At the moment, we have to make lots of assumptions about what’s going on in tumour cells. We can take biopsies and look at the different cell types, how aggressive they are, their genetic structure and so on, but we can only guess what’s happening to a tumour at a functional level. Functional information is important for helping us determine how best to treat the cancer – and hence how we can personalise treatment for a particular patient. Using PET/MR, we can get real-time information for that patient’s specific tumour and not have to assume it is behaving in the same way as the last hundred tumours we’ve seen.”

̽��ֱ��PET/MR scanner will begin operation at the start of November, when it will initially be used to study oxygen levels and blood flow in the tumours of breast cancer patients and in studies of brain inflammation in patients with Alzheimer’s disease and depression.

Hyperpolarizer

̽��ֱ��third new piece of imaging equipment to be installed is a GE Healthcare hyperpolarizer, which is already up and running at the facility.

MRI relies on the interaction of strong magnetic fields with a property of atomic nuclei known as ‘spin’. By looking at how these spins differ in the presence of magnetic field gradients applied across the body, scientists are able to build up three-dimensional images of tissues. ̽��ֱ��hyperpolarizer boosts the ‘spin’ signal from tracers injected into the tissue, making the MRI measurement much more sensitive and allowing imaging of the biochemistry of the tissue as well as its anatomy.

“Because of underlying genetic changes in a tumour, not all patients respond in the same way to the same treatment,” explains Professor Kevin Brindle, who leads research using the hyperpolarizer. “Using hyperpolarisation and MRI, we can potentially tell whether a drug is working, from changes in the tumour’s biochemistry, within a few hours of starting treatment. If it’s working you continue, if not you change the treatment.”

̽��ֱ��next generation of imaging technology, newly installed at the ̽��ֱ�� of Cambridge, will give researchers an unprecedented view of the human body – in particular of the myriad connections within our brains and of tumours as they grow and respond to treatment – and could pave the way for development of treatments personalised for individual patients.

By bringing together these scanners, the research expertise in Cambridge, and the latest in ‘big data’ informatics, we will be able to do sophisticated analyses that could revolutionise our understanding of the brain – and how mental health disorders and dementias arise – as well of cancers and how we treat them

Ed Bullmore

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

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Watching the death throes of tumours

cjb250 — Wed, 25 Feb 2015 12:49:11 +0000

There was a time when diagnosing and treating cancer seemed straightforward. Cancer of the breast was breast cancer, for example, and doctors could only choose treatments from a limited arsenal.

Now, the picture is much more complicated. A study published in 2012, led by Carlos Caldas, showed that breast cancer was actually at least ten different diseases. In fact, genome sequencing shows that even one ‘type’ of breast cancer differs between individuals.

While these developments illustrate the complexity of cancer biology, they also offer the promise of drugs tailored to an individual. Chemotherapy is a powerful, but blunt, instrument – it attacks the tumour, but in doing so also attacks several of the body’s other functions, which is why it makes patients so ill. ̽��ֱ��new generation of cancer drugs aim to make the tumour – and not the patient – sick.

But telling if a patient is sick is easy; telling if the tumour is sick is more challenging. “Conventionally, one assesses whether a tumour is responding to treatment by looking for evidence of shrinkage,” explained Professor Kevin Brindle from the Cancer Research UK (CRUK) Cambridge Institute, “but that can take weeks or months. And monitoring tumour size doesn’t necessarily indicate whether it is responding well to treatment.”

Take brain tumours, for example. They can continue to grow even when a treatment is working. “ ̽��ֱ��thing is that a tumour is not just tumour cells. There are lots of other cells in there, too.”

For some time now, oncologists have been interested in imaging aspects of tumour biology that can give a much earlier indication of the effect of treatment. Positron emission tomography (PET) can be used for this purpose. ̽��ֱ��patient is injected with a form (or analogue) of glucose labelled with a radioactive isotope. Tumours feed on the analogue and the isotope allows doctors to see where the tumour is.

An alternative technique that doesn’t expose the patient to ionising radiation is magnetic resonance imaging (MRI), which relies on the interaction of strong magnetic fields with a property of atomic nuclei known as ‘spin’. ̽��ֱ��proton spins in water molecules align in magnetic fields, like tiny bar magnets. By looking at how these spins differ in the presence of magnetic field gradients applied across the body, scientists are able to build up three-dimensional images of tissues.

In the 1970s, scientists realised that it was possible to use MR spectroscopy to see signals from metabolites such as glucose inside cells. “Tumours eat and breathe. If you make them sick, they don’t eat as much and the concentration of some cell metabolites can go down,” said Brindle.

Around the same time, scientists hit upon the idea of enriching metabolites with a naturally occurring isotope of carbon known as carbon-13 to help them measure how these metabolites are used by tissues. But carbon-13 nuclei are even less sensitive to detection by MRI than protons, so the signals are boosted using a machine developed by GE Healthcare, called a hyperpolariser, which lines up a large proportion of the carbon-13 spins before injection into the patient.

In 2006, Cambridge was one of the first places to show that this approach could be used to monitor whether a cancer therapy was effective or not. Combined with the latest genome sequencing techniques, this could become a powerful way of implementing personalised medicine. What’s more, because no radioactive isotopes are involved, an individual could be scanned safely multiple times.

“Because of the underlying genetics of the tumour, not all patients respond in the same way, but if you sequence the DNA in the tumour, you can select drugs that might work for that individual. Using hyperpolarisation and MRI, we can potentially tell whether the drug is working within a few hours of starting treatment. If it’s working you continue, if not you change the treatment.”

̽��ֱ��challenge has been how to deliver the carbon-13 to the patient. ̽��ֱ��metabolite has to be cooled down to almost absolute zero (–273°C), polarised, warmed up rapidly, passed into the MRI room and injected into the patient. And as the polarisation of the carbon-13 nuclei has a half-life of only 30–40 seconds, this has to be done very quickly.

This problem has largely been solved and, with funding from the Wellcome Trust and CRUK, Brindle and colleagues will this year begin trialling the technique with cancer patients at Addenbrooke’s Hospital. If successful, it could revolutionise both the evaluation of new drugs and ultimately – and most importantly – the treatment of patients.

“Some people have been sceptical about whether we could ever get a strong enough signal. I’m sure we will. But will we be able to do something that is clinically meaningful, that is going to change clinical practice? That’s the big question we hope to answer in the coming years.”

Inset image: Kevin Brindle and Stefanie Reichelt.

A clinical trial due to begin later this year will see scientists observing close up, in real time – and in patients – how tumours respond to new drugs.

Using hyperpolarisation and MRI, we can potentially tell whether the drug is working within a few hours of starting treatment

Kevin Brindle

Kevin Brindle; published in Nature Medicine (2014) 20, 93-97

An abdominal tumour (outlined in white) 'feeding on' carbon-13-labelled glucose (orange) provides a means of testing when cancer drugs are effective enough to affect the health of the tumour

Lighting up the body

In many ways, light microscopy is a much better imaging technique than MRI and PET to study the nature of biological materials: it provides higher resolution and higher specificity as fluorescent markers can be used to highlight specific cancer cells and molecules in cells and tissues.

However, as Dr Stefanie Reichelt, Head of Light Microscopy at the Cancer Research UK Cambridge Institute, points out, there’s an obvious drawback: “Light doesn’t penetrate tissue, so we can’t see deep beneath the skin.”

Reichelt and colleagues are working on ways to correlate light microscopy with Kevin Brindle’s medical imaging techniques. One technique that shows promise for bridging the gap is light sheet microscopy, a fluorescence microscopy technique with an intermediate optical resolution.

A thin slice of the sample is illuminated perpendicularly to the direction of observation; this reduces photo damage, thus allowing high-speed, high-resolution, three-dimensional imaging of live animals and tissues.

“ ̽��ֱ��key for us is to be able to image whole biopsy samples or tumours rapidly and at a high level of detail.”

Reichelt is also exploring new techniques such as Coherent Anti-Raman Stokes, which uses the nuclear vibrations of chemical bonds in molecules. This can provide a highly specific but label-free imaging contrast. This capability will allow the investigation of unlabelled live tissues from tumour biopsies with high specificity.

̽��ֱ��text in this work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page. For image rights, please see the credits associated with each individual image.

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Watching cancer cells eat, breathe and die

bjb42 — Mon, 04 Jan 2010 14:27:46 +0000

Increasing the speed and sensitivity of detecting how tumour cells are responding to treatment is something of a Holy Grail in the field of oncology. Treatment response is still largely assessed by looking for a reduction in tumour size using magnetic resonance imaging (MRI) or X-ray computed tomography. But many tumours may take weeks or even months to show evidence of regression and, in some cases, may not regress at all despite a positive response to treatment. How can an earlier indication of response be achieved so that clinicians can select the best treatment for an individual patient?

New techniques are being pioneered in Cambridge to ‘see’ tumour cells as never before. Research in Professor Kevin Brindle’s laboratory is developing a variety of clinically applicable, non-invasive, imaging techniques that measure tumour cells ‘eating, breathing and dying’.

Spin doctor

One approach under investigation by the Brindle lab is based on MRI. Although this technique has been around since the 1970s, the new imaging method has a crucial difference – instead of detecting the distribution and properties of water protons in tissue, which conventional MRI does, the new approach detects with much greater sensitivity than ever before the small molecules in tissues that are fundamental to their biochemistry. These are the carbon-based metabolites involved in producing energy and in making the constituents of the cell; a change in how these metabolites are being used can signal that an effective therapy is starting to kill the cells.

̽��ֱ��problem with carbon-based molecules is that they are present in tiny amounts compared with the protons in tissue water, making them hard to detect and almost impossible to image at high resolution. To overcome this, the Brindle group has been collaborating with GE Healthcare to develop a technique that increases MRI sensitivity by more than 10,000 times.

To achieve such a dramatic increase in sensitivity, the scientists have turned to nuclear spin hyperpolarisation. Before intravenous injection, a molecule labelled with an MR isotope of carbon is hyperpolarised so that a large proportion of the carbon nuclear spins line up with the magnetic field, as opposed to only a few in a million in a conventional MR experiment. ̽��ֱ��resulting gain in sensitivity means that the researchers can watch how the hyperpolarised carbon is metabolised by tumours, using this as a read-out for living and dying cells. Data published recently have shown how well this technique works for monitoring treatment response, and the first clinical trials are planned to start in 2010.

Personalising medicine

Different tumours are likely to require different imaging methods. With recent funding from the Leukaemia and Lymphoma Society, a new study has just begun in which several of the imaging methods under development in the Brindle group are being validated in models of lymphoma, so that the best reagents and protocols can be selected for future clinical trials.

Improved imaging methods are not only useful in the clinic, but will also be invaluable for early stage clinical trials of new drugs, where the need to establish whether new treatments are working is particularly acute. Professor Brindle is working with Professor Duncan Jodrell and Dr David Tuveson at the Cancer Research UK Cambridge Research Institute to develop imaging methods that allow treatment responses in individual patients to be measured immediately. Because patients with similar tumour types can show markedly different responses to the same therapy, imaging will be an important component of the armoury of ‘personalised medicine’, enabling the most effective treatment to be tailored to specific patients.

For more information, please contact Professor Kevin Brindle (kmb1001@cam.ac.uk) at the Department of Biochemistry and the Cancer Research UK Cambridge Research Institute/Li Ka Shing Centre. This research was published in Proceedings of the National Academy of Sciences (2009) 106, 19801–19806 and was funded principally by Cancer Research UK, with material support from GE Healthcare.

Cancer cells can now be viewed as never before, thanks to cutting-edge imaging tools being developed in Cambridge.

Kevin Brindle

Lymphoma

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CRI: linking the laboratory to the cancer clinic

ns480 — Fri, 01 May 2009 12:58:17 +0000

̽��ֱ��CRI is the most recent of five comprehensive research institutes core funded by Cancer Research UK. Housed in the magnificent, custom-built, £50 million Li Ka Shing Centre, the Institute is located on the Cambridge Biomedical Campus. With more than 250 scientists in 19 research groups, it is one of the largest cancer research facilities in Europe.

Officially opened in early 2007, the Institute is already internationally acclaimed for the high calibre of its research. ‘We’ve been able to hit the ground running,’ said Director Professor Sir Bruce Ponder, ‘and this is largely because the funding we receive from Cancer Research UK means that we can guarantee salary, staff, laboratory space and core facilities, so the individuals we recruit have minimal interruption to research as they set up their laboratories.’

Group leaders have been carefully chosen with complementary research interests in mind – roughly half are engaged in the study of fundamental aspects of cancer cell biology and half in technology-based or clinical-based research; over a third are clinically qualified. Many of the group leaders hold joint appointments with the Hospital, the ̽��ֱ�� (seven within the Department of Oncology) or research institutes on the Cambridge Biomedical Campus. CRI’s location on the Campus offers outstanding opportunities for such interaction because of its proximity to the Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust (Addenbrooke’s), the ̽��ֱ�� School of Clinical Medicine and its associated institutes, and the Medical Research Council (MRC) Laboratory of Molecular Biology and four MRC Units.

All of these interactions are crucial to the success of the Institute, as Professor Ponder (who is also Head of the Department of Oncology) explained: ‘It’s no good creating a freestanding institute that’s got a ‘moat’ around it – we work hard to be fully connected with Cambridge’s research environment and the Hospital, both to expand our intellectual base and to ensure that laboratory advances are translated into benefits to cancer patients as quickly as possible. ̽��ֱ��joint appointments really make these interactions work, and is another reason we’ve been able to get off the ground so quickly.’

Recent research highlights include the discovery of precisely why some women develop resistance to the breast cancer drug tamoxifen. Dr Jason Carroll, who leads the Nuclear Receptor Transcription Laboratory, explained: ‘We knew that women developed resistance to tamoxifen but previously our understanding of why this occurred could be compared with trying to fix a broken car without knowing how the engine worked. Now we understand how all the engine parts operate and we can try to think about ways to make repairs.’

Professor Kevin Brindle, who leads the Molecular Imaging Laboratory, has developed a way of scanning the body using magnetic resonance imaging to a level of precision that could be used to detect cancer earlier, as well as for the evaluation and design of novel cancer therapies. Dr David Tuveson has set up a facility in the clinic for treating patients with pancreatic cancer and a matching experimental system in the laboratory to test and refine potential new treatments.

To strengthen cancer research collaborations across Cambridge, a virtual community has arisen with the CRI as its nucleus. ̽��ֱ��Cambridge Cancer Centre (CCC) forges links between cancer researchers in the biological and physical sciences, clinicians and local biotech companies.

‘CCC creates an environment in which basic research can have a practical application, collaborative projects can be developed, and new interdisciplinary work can be pump-primed,’ said Professor Ponder, who chairs the CCC Steering Committee. ‘We’re now moving into a new phase with the CCC in which we’re identifying collaborative research themes and developing the organisational structures that will help to drive them forward.’

What happens next at the CRI? Research at the Institute will bed down and integrated programmes will continue to develop. ̽��ֱ��top floor of the Institute is being kept in reserve. ‘In a few years’ time,’ said Professor Ponder, ‘the science at the Institute will have matured to the point where we will be able to make intelligent choices about what we need to add. My colleagues and I believe that we have something really special at the CRI, and I’m delighted to say that the funders and local community share our enthusiasm.’

For more information, please visit www.cambridgecancercentre.org.uk

̽��ֱ��Cambridge Research Institute (CRI) is driving the development of new approaches for the early detection, prevention and treatment of cancer.

We work hard to be fully connected with Cambridge’s research environment and the Hospital, both to expand our intellectual base and to ensure that laboratory advances are translated into benefits to cancer patients as quickly as possible.

Professor Sir Bruce Ponder

CRI

Cambridge Research Institute

Cancer Research UK

Formed in 2002 by the amalgamation of the two largest UK cancer charities – the Cancer Research Campaign and the Imperial Cancer Research Fund – Cancer Research UK continues a century-long history of funding cancer research. Its annual research budget funds the work of over 4500 scientists, doctors and nurses across the UK, including research at a number of specialised institutes and centres. ̽��ֱ��most recent of the core-funded institutes, the Cambridge Research Institute (CRI), is a flagship research enterprise located on the Cambridge Biomedical Campus.

In 2007–8, Cancer Research UK spent just over £31.5 million on laboratory research and clinical trials in Cambridge; around £17.5 million of this annual research spend provided core funding for the CRI.

Funding by Cancer Research UK covers all aspects of cancer research, from understanding fundamental cancer cell biology to large epidemiology studies across entire populations of people, as well as training the next generation of research scientists. Some examples in Cambridge include:

Several programme grants and a significant element of core funding to the Wellcome Trust/Cancer Research UK Gurdon Institute, where research is helping to uncover what goes wrong when a cell becomes cancerous, by investigating the processes that ensure that cells function correctly during normal development.
Funding the two UK arms of the largest study of diet and health ever undertaken – the European Prospective Investigation into Cancer and Nutrition (EPIC) – a long-term study of more than half a million people in 10 European countries. ̽��ֱ�� ̽��ֱ�� of Cambridge manages the Norfolk arm of EPIC, which has recruited more than 30,000 people.
Scientists at the Strangeways Research Laboratory and Department of Oncology, who are searching for genes that increase cancer risk and investigating how the effects of the genes combine with lifestyle factors to cause cancer.
Cancer Research UK PhD Training Programme in Medicinal Chemistry, a collaborative initiative that brings together research groups with expertise in synthesis chemistry, pharmacology, biochemistry and cancer biology to train synthesis chemists to PhD level (www-medchem.ch.cam.ac.uk).

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