A single injection of a modified protein can temporarily open the brain’s protective barrier around tiny tumours, letting chemotherapy drugs reach them before they grow large. This matters because brain metastases—cancers that spread from elsewhere in the body—are almost impossible to treat early. The blood-brain barrier blocks most drugs, so patients are typically diagnosed only after tumours have grown large enough to cause symptoms, by which point life expectancy is 3–9 months. The team has already shown in animal models that a protein called TNF, when injected at very low doses, makes blood vessels near metastases leaky without affecting healthy brain vessels. They have now engineered a more selective version that targets only the TNFR1 receptor, reducing the risk of side effects. If this approach works in humans, it could transform how brain metastases are treated. Instead of waiting for tumours to become visible and symptomatic, doctors could give patients a drug combination as soon as a primary cancer is diagnosed—potentially catching and treating secondary tumours when they are still microscopic. The method is designed to work with any therapeutic drug, not just one specific compound, and the team is testing it against breast, lung, and melanoma cancers, all of which commonly spread to the brain. At the end of this project, they will be ready to apply for approval to begin an early-phase clinical trial.
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The spread of cancer from a primary tumour to the brain remains one of the greatest challenges in cancer treatment, and life expectancy from diagnosis is typically 3-9 months. Blood vessels in the brain are much less permeable than those elsewhere in the body and possess what is known as the blood-brain barrier, which prevents the movement of drugs from the blood into the brain. This blood-brain barrier is one of the main reasons why early treatment of secondary brain tumours (metastases) is not possible. However, we know that the earlier treatment begins, the more effective it is likely to be. We are interested, therefore, in finding ways to make the blood vessels close to brain metastases leaky, particularly when they are still very small. We have recently shown in experimental models that by injecting a protein called TNF into the blood we can make the vessels close to brain metastases leaky, whilst leaving the rest of the vessels in the brain intact. This approach works because the blood vessels associated with these secondary tumours are different to normal brain blood vessels and express a protein receptor (TNFR1). TNF is able to interact with this receptor and, in doing so, causes the vessels to become leaky. We have shown that using this approach we can selectively deliver common cancer therapies to brain metastases when they are still very small. TNF can be toxic at high doses, but the amounts we are using are much lower than this and, therefore, would be tolerable. Nevertheless, by developing a more selective protein that interacts only with TNFR1, and no other protein receptors, we have been able to further decrease the amount needed and reduce the likelihood of toxic side-effects. We now aim to show that it is possible to increase delivery of a clinically used drug into brain metastases by administering it together with the new TNFR1-selective protein, and that the therapeutic effect of the drug is enhanced as a consequence. Next we will optimise production of the TNFR1-selective protein for human use and undertake pre-clinical toxicology and stability tests to support a downstream clinical trial. We also aim to show that our approach to making vessels in brain metastases leaky is effective for several different tumour types (breast, lung and melanoma), all of which are at high risk of spreading to the brain, to further support clinical translation. The huge advantage of this approach to overcoming the blood-brain barrier, compared to alternative solutions, is that delivery of any therapeutic drug to these tiny brain tumours is possible once the vessels are leaky. At the end of this project, we will be ready to apply for authorisation to undertake an early phase clinical trial; within this trial we will obtain preliminary information on whether our TNFR1-selective protein enables improved treatment of brain metastases.
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