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For Brain Tumour Awareness Month, Vanessa Johanssen talks about her work and how their research has helped to find brain tumours when they're small enough to treat.

bEnd.3 cells expressing VCAM-1 (red) and VCAM-1 targeted microbubbles (green). Image courtesy reproduced with permission from Dr Alec Thomas IBME

How do you find a needle in a haystack? ...

Brain tumours are devastating. Typical prognosis is a mere 3-9 months after a diagnosis based on an MRI scan.

The problem is one of size. An MRI scan can detect a tumour that is larger than 0.5-1 cm in diameter. 

The reason tumours need to be of macroscopic size in order to be detected by MRI is due to the protective blood-brain barrier (BBB), which tightly regulates molecular entry into, and exit from, the brain.

When brain tumours are small they grow behind the BBB.  This means that we cannot get either drugs that would treat the tumour, or contrast agents that would cause it to show up clearly on the MRI scan, into these tiny tumours. The BBB only begins to breakdown when the tumour reaches 0.5-1 cm in diameter allowing diagnostic imaging agents and therapeutic drugs to cross the BBB.

A method that could detect tumours before BBB breakdown and also enable localised, selective permeability of the BBB at the tumour site would allow earlier detection, and reduce damage to surrounding healthy brain tissue whilst enabling earlier treatment and improved prognosis.

... Target a well tuned magnet

Prof Nicola Sibson developed a method for detecting brain tumours early.  Her idea was to use an imaging agent that did not need to cross the BBB.

One of the characteristics of solid tumours is that they like to provoke inflammation; the body’s response to injury or infection. During inflammation, markers develops on the inside walls of blood vessels.  One such marker is called the vascular cell adhesion molecule 1 (VCAM-1).

Blood vessels are lined with a single layer of endothelial cells. When stimulated by cytokines (the chemical signals of inflammation) VCAM-1 expression is up-regulated on this layer of endothelial cells and it acts like a Velcro hook and loops to capture white blood cells, which will be needed as part of the inflammation response.

Prof Sibson found that VCAM-1 expression is up-regulated very early in the development of a brain tumour.  This observation allowed her to develop an imaging agent that stuck to the Velcro hooks of VCAM-1, which in turn enabled detection of brain tumours as small as approximately 0.1 mm in diameter. This is only possible because the imaging agent does not have to cross the BBB, but detects the VCAM-1 on the inside of the blood vessels.

We can find it; how do we treat it?

Now we can find very small tumours can we treat them? Prof Sibson has teamed up with a biomedical engineer Prof Eleanor Stride from the Institute of Biomedical Engineering to make this possible.

Prof Stride has developed a new method for delivering cancer drugs.  She wraps the drugs into microbubbles. The bubbles, that are much smaller than a red blood cell, are coated with a biocompatible shell that keeps the drugs from interacting with cells until they’re needed. Once the bubbles are in the right place, ultrasound is used to activate the bubbles, releasing the drug and “pumping” it into the tumour.

Profs Sibson and Stride are combining their expertise and capitalising on this specific VCAM-1 upregulation in order to develop microbubbles with anti-VCAM-1 antibodies. The bubbles stick to the VCAM-1 Velcro at the site of very early tumours. Ultrasound is then applied to deliver the drug into the tumour across the BBB.

Our results look promising. I am still astonished by the reversible BBB breakdown that ultrasound can deliver non-invasively.  It is very exciting to be involved with a cross-disciplinary team that is already close to trialling this technology in patients to hopefully allow for rapid translation and earlier and more effective treatment of brain tumours.