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Largest-ever brain cancer clinical trial underway

A clinical trial for brain cancer patients has recruited more UK participants than ever for a study of its kind.

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Working with seven UK hospitals, including the National Hospital for Neurology and Neurosurgery (NHNN), part of UCLH, 119 patients with glioblastoma have been recruited in just over two years to the IPI-GLIO trial.

Glioblastoma is a very aggressive brain tumour with around 2,200 cases diagnosed each year in England (and around 3,200 across the UK). The average survival time is around 15 months, with fewer than 10 per cent of patients alive five years after diagnosis following standard treatment.

In the Phase II Clinical trial, following standard treatment for glioblastoma of surgery, where appropriate, radiotherapy and chemotherapy, patients were given ipilimumab, a drug that has seen significant improvements in survival rates for people with melanoma skin cancer. The drug blocks a key regulator in the immune system, making the immune system more active.

Study participants will be followed up over the next 18 months and the findings will be presented to the American Society of Clinical Oncology in May 2023.

The trial is designed by Dr Paul Mulholland, who leads the UCL Glioblastoma Research Group, and has been funded by the National Brain Appeal and supported by the UCLH NIHR Biomedical Research Centre.

“Now that we have recruited the 119 patients to the IPI-GLIO trial we have planned a programme of trials so this work can continue. We have established a Glioblastoma Research Group and laboratory at UCL Cancer Institute,” says Dr Mulholland.

“We are bringing together the newest drugs from the pharmaceutical industry together with the latest developments in scientific research to try to find a cure for this devastating disease.

“It cannot be underestimated how significant The National Brain Appeal’s decision to fundraise for this trial has been. I am so grateful to everyone who has donated and those continuing to fundraise.”

The IPI-GLIO trial represents the UK’s first large-scale, charitably funded, immunotherapy trial for NHS patients recently diagnosed with glioblastoma brain cancer; the patient cohort is the largest ever number of UK participants in a brain cancer clinical trial.

It is sponsored and managed by the University of Oxford. The pharmaceutical company Bristol Myers Squibb also contributed to part funding the study and provide the drug ipilimumab.

Funds raised by the charity have enabled the trial to take place in seven centres around the UK, in Cambridge, Edinburgh, London (UCLH and Guy’s Hospital), Manchester, Middlesex and Oxford.

Brain injury

High-res computer modelling to shed new light on TBI impact

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Researchers have created a traumatic brain injury (TBI) computer model that maps blood vessels in a rat brain in the highest resolution yet.

The team at Imperial College London say the models could help improve understanding of how blood vessels are affected by TBI, as well as its effects on the protective layer encasing them known as the blood-brain barrier (BBB), which protects the brain from harmful circulating molecules and pathogens.

If the methods translate well onto human brains, Imperial say they could also help improve understanding of how TBIs develop and how best to treat and protect against them.

The simulations could even help to replace animal models of TBI, potentially reducing the use of animals in brain research.

TBIs are the most common cause of chronic disability in under 40-year-olds and result from severe blows or jolts to the head. 

Beginning at the site of impact, mechanical forces travel in waves through the brain, twisting, stretching, and shearing brain structures as the injury cascades. These forces are known to affect blood vessels, but the finer details of the relationship between mechanical forces and vascular injury are yet to be established.

Now, researchers at Imperial have created a computer model of TBI which maps the network of vessels in the brain – called the vasculature – in the highest resolution yet, incorporating rat brain vessels just 10 microns in diameter.

Using the models, they found that adjacent blood vessels sustain profoundly different levels of stress depending on their alignment with neighbouring ones.

Blood vessels at 90 degree angles to others were less likely to be damaged, and vessels could be stretched to up to 14 per cent of their original length without injury, while stretching by more than this amount would result in injury.

Lead author Dr Siamak Khosroshahi, who conducted the work while at Imperial’s Dyson School of Design Engineering, says: “Our unique approach explains the unrecognised role of the vascular anatomy and shear stresses in how large forces cascade through the brain. This new understanding could contribute to improving TBI diagnosis and prevention.”

The degree to which the BBB lets molecules into the brain is known as permeability. The barrier can become more permeable after injury, making it more likely to let pro-inflammatory molecules reach the brain and usher in further injury.

By using rat models of TBI, the authors demonstrated that greater BBB permeability occurs in TBI as a result of disruption of the vasculature, and that this is most evident soon after injury.

From this information they created brain models digitally in high enough resolution to highlight the vasculature. They found that the computer models allowed them to accurately predict the distribution of stress in the small blood vessels of the rat brains. The models also allowed them to slow down time to look at the details of TBI more closely.

Senior author Dr Mazdak Ghajari, also of Imperial’s Dyson School of Design Engineering, says: “Injury happens in a fraction of a second, making it hard to observe exactly what goes on. By slowing down the process, we can pinpoint exactly which brain areas sustain the most damage and go some way to understanding why.”

The new, high resolution computer simulations could provide a blueprint for studying TBIs using more computers and fewer animal models, in line with the principles of Replacement, Reduction and Refinement (the 3Rs) in animal research.

The researchers say their models could also provide a more objective way to assess protection systems like helmets. Future studies on humans that include detailed reconstructions of the biomechanics of TBI are also needed to confirm the findings before using them to predict injury risk in humans.

The improved understanding of the BBB could also help further research into drug delivery of brain-specific medicines.

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Interviews

‘The day we can say this company is successful is the day we save a life’

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Hailed as the future of cancer diagnostics, Dxcover is set to revolutionise healthcare by pioneering a new test to diagnose cancer more quickly, simply and cost-effectively than ever before. CEO Dr Mark Hegarty and chief technology officer Dr Matthew J Baker discuss their pioneering work to date in brain cancer detection

 

Through the AI-led analysis of a single drop of blood, it is possible to detect brain cancer.

Having been verified through two groundbreaking clinical studies, the Dxcover Brain Cancer liquid biopsy, the first of its kind in the world, is now set to go into pivotal trials with a view to commercialisation in 2024 – paving the way to save lives and improve quality of life globally through the earlier diagnosis of cancer. 

With the creation of the Dxcover Platform – which combines novel hardware with artificial intelligence algorithms to analyse a patient’s blood – and its patented Drop Dry Detect method of detecting cancer, a process which currently may take eight weeks or more to fully diagnose can be fast-tracked into a matter of minutes. 

At a time when COVID-19 has increased waiting times for cancer diagnosis and treatment dramatically, the creation of a technology which simplifies and quickens the process of diagnosis is being widely supported, with £5.1m raised to date to progress its work. 

And its application is also set to be extended into other forms of cancer, with the Scottish startup currently developing liquid biopsies for individual cancers through its Dxcover Cancer project, as well as a multi-cancer test which could detect many forms of the disease. 

The business, which began life as a research project at the University of Strathclyde and spun out in 2019, plans to launch its first life-saving technology initially in the United States pending the success of the pivotal trial and regulatory approval process. 

Dxcover – which recently rebranded from ClinSpec Diagnostics, and now also has the tagline The Future of Cancer Diagnostics – has also expanded into laboratory and office space in Glasgow three times the size of its former base, to help facilitate its ongoing growth and further development of its pioneering work. 

“We work on the basis that every day counts – for patients who need a diagnosis and treatment, for doctors looking for better diagnostic methods, for healthcare service providers who want to do things more efficiently,” says Dr Mark Hegarty, CEO of Dxcover. 

“But the day we will be able to say this company is successful is the day we can say we have saved a life.” 

The company’s journey towards its lifesaving aims began in 2012, when Dr Matthew J Baker began his first experiments to establish whether a biopsy could be analysed by AI to distinguish between cancer and non-cancer diagnoses. 

Once the potential of his work was realised, Dr Baker – an inventor with over 18 years’ experience in the field of clinical spectroscopy – patented his spectroscopic liquid biopsy technology and was introduced to Dr Hegarty by the University, who were keen to bring in the expertise to support the development of such game-changing research into a viable business which could apply its technology around the world. 

Dr Hegarty, with over 20 years of experience in supporting startups and healthcare products into international successes, immediately recognised the potential of what Dr Baker had created – and the two men also realised they could work together effectively – “We both like fast response times and are not afraid of hard work,” says Dr Hegarty. 

And from there, Dxcover has progressed into a venture with the clear potential to transform cancer diagnosis as we know it, leading the way in the marketplace with its innovation.

“Liquid biopsy is a hot topic, it’s a cutting-edge technique which holds great promise,” says Dr Baker, chief technology officer of the business. 

“Most research focuses on genomic data, the big US companies are focusing on the genetic information from the tumour – but ours is different and looks at the entire signal from the serum. We don’t just look at tumour markers, we look at the human response. That is then teased apart by machine learning. 

“There isn’t really another company out there with our approach, and we hold the patents for the diagnosis of all cancers, so no-one can do exactly what we do. Our platform methodology can handle any serum sample, it’s exactly the same analysis, so there’s great potential.”

Supported by a hugely capable and growing senior leadership team – its most recent appointment being operations director Dr David Eustace, an experienced figure in regulated diagnostic product development – Dxcover is working to a clear plan of how to build its cancer diagnosis offering.  

“The most important thing at this stage is being able to add more data. Everything depends on the quality and value of the data. The growth of our data set is the key thing,” says Dr Hegarty. 

“Our Dxcover Cancer project is a multi-cancer study aimed at developing a test to detect several cancers from a single blood sample, and also to indicate the organ of origin. That would be very beneficial for clinicians are often faced with vague symptoms, making it very difficult to pin down whether a person has cancer and the type of cancer.”

While its initial target for Dxcover Brain Cancer rollout will be the United States, the company continues to be based in its native Scotland, where it has progressed so strongly, benefiting from the backing of the Scottish Enterprise High Growth programme in its earliest days, which the team credit with being crucial in its development.  

“We may well add an office in Europe as we progress, and will definitely have an office in the States sooner rather than later,” says Dr Hegarty. 

“We are also looking to attract a highly-experienced set of US advisors, which we believe will be key to our growth.”

Dr Baker adds: “Being based in Glasgow gives us access to great young talent coming from the universities, we haven’t had any issues in employing the next generation of spectroscopists. For me, having our R&D hub here we benefit from the health tech ecosystem in Scotland, and it fits perfectly with what we want to do.

“We have a great team and strong values and we’re all working towards the same thing – saving lives.”

 

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Brain injury

Research reveals damage repair during brain injury

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Brain disease

A new signalling pathway has been discovered that could shed light on damage repair during brain injury. 

The new understanding of what causes neural cells to enter divisions after damage in the brain is a “valuable opportunity” to potentially prevent neuronal death or neurodegeneration following injury. 

The research, led by the University of Plymouth, explores how most human cells are able to repair damage by dividing at wounds –  but mature nerve cells, or neurons, will most probably die if they attempt division. This happens during brain injury or in conditions including Alzheimer’s Disease. 

But now, the study has uncovered a pathway that has shed new light on how these divisions may be triggered. The research focuses on intracellular structures called microtubules – which are found in most animal cells, and can be damaged by a build-up of a protein called Tau in the brain during Alzheimer’s.

The study was conducted in fruit flies, with comparison to postmortem brain samples of Alzheimer’s patients, with findings showing that when the microtubules of neural cells in fruit flies are damaged, division is triggered via activating the small signalling kinases, Tak1 and Ik2. 

Activation of these molecules can also be seen in brains of people with Alzheimer’s.

“While other scientists are exploring Tau and how it builds up, we’re looking more at what happens to the cell after it has been damaged,” says Dr Torsten Bossing, of Plymouth Institute of Health and Care Research (PIHR), who led the research. 

“The fact that the identified two signalling kinases are found alongside a build-up of Tau in post mortem brains of Alzheimer’s Disease patients suggests that the mechanism identified using fruit flies may act similarly in humans. So we want to further our studies by using cultured human neurons next. 

“Ultimately we want to prevent this abnormal cell division entry process from happening in the first place. It’s an exciting piece of work, which we look forward to progressing.”

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The team say that by understanding how the damaged microtubules behave, the potential exists to prevent neuronal death following brain injury, or upon neurodegeneration, such as in Alzheimer’s.

While the research took place in fruit flies, the team tested the applicability of their results by making fly neural cells express human Tau, and also examining post mortem human brain samples from Alzheimer’s patients.

Abnormal human Tau destroys microtubules in both flies’ and Alzheimer’s brains, and interestingly can trigger the same signalling cascade as discovered in fly neural cells after microtubule damage.

The researchers also found that higher levels of Tau accumulation correlated to a greater frequency of neurons attempting to divide and neuronal death, but have not yet established a direct link or cause.

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