Brain Research UK - Royal College of Surgeons of England joint research fellowship
Neurosurgical trainee Milo Hollingworth was awarded this joint research fellowship in 2022, to take forward research aimed ultimately at improving the way in which drugs are delivered to the site of brain tumours.
The treatment of brain tumours is complicated by the difficulty of getting chemotherapy drugs into the brain at a high enough concentration. The blood-brain barrier is a vital protective mechanism, protecting the brain from toxins in the blood. However, it also hampers the passage of drugs – which has been an important factor of failed therapies in the past, not just for brain tumours but other neurological conditions.
Milo’s research aimed to address this problem by developing new drugs that are effective in the treatment of brain cancer AND can be seen on MRI, enabling location, concentration and activity to be tracked in real-time.
When administering drugs for the treatment of brain diseases it is important to know where the drugs are going and in what concentration. For a drug to work, it must be available at the site of action in its active form at the correct concentration and for an appropriate amount of time.
However, the brain is a black box when it comes to drug therapy: we can put drugs in and we can measure outcomes (such as changes to the tumour, and length of survival), but we can't see what is happening within the brain. If there is no effect, we don't know why. Is it that the drug itself isn't effective? Is it because the drug isn't getting to the right target, in a high enough concentration?
Milo and his colleagues (Dr Ruman Rahman, Dr Pete Harvey and Rhian Griffiths) have begun to address these questions by developing drugs that are magnetic resonance imaging (MRI) active – that is, drugs that are modified with molecules that are visible using MRI. When injected into the brain, therefore, their location, concentration and activity can be visualised and monitored.
In particular, the team has developed an MRI-active version of Olaparib, a targeted drug that is already used in the treatment of some cancers, and which has shown some effectiveness against certain brain tumours in laboratory testing. As part of this project, the team established a clinical trial that has recruited 13 patients (and counting) to visualise glucose metabolism in glioblastoma multiforme (the most common primary brain cancer in adults); developed an MRI-active drug that could drive pharmaceutical investment, accurately visualise drug concentrations directly in time and space, and kill cancer cells in-vitro; and a simulation platform to allow troubleshooting of clinically relevant problems to aid translation of this technology without the need for animal research.
Patients at Nottingham University Hospitals are being offered the opportunity to join the clinical trial, which has been met with resoundingly positive feedback. The team have already been able to demonstrate that their imaging technique is feasible and comfortable for patients and, with increasing patient numbers, are hopeful that they can identify unique metabolic signatures in brain tumours that will avoid the need for biopsy in certain patients and can predict treatment response more accurately than conventional imaging techniques.
The team’s ‘proof of principle’ preclinical work demonstrates for the first time that a drug can been directly labelled in such a way that it can be visualised non-invasively without affecting its biological function. This next-level technique could allow researchers and clinicians to reignite and repurpose off-patent drugs and fine-tune drug dosing and delivery techniques to target brain tumours and other difficult to treat diseases. In the future, this technology could potentially help optimise dosing schedules for patients, helping to improve efficacy and reduce toxicity.
Milo says: “My project would not have been possible without the support and generosity of Brain Research UK and Royal College of Surgeons. The scheme offers essential support for the surgical leaders of the future… [and] is the only scheme with the scope to stimulate innovative and original research for trainee surgeons across the UK.”
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