Towards a treatment for venous malformation?

Angiomas, vascular malformations that can provoke numerous symptoms, afflict approximately 6,000 people in Belgium. For 20 years, Dr Laurence Boon, coordinator of the Centre for Vascular Anomalies of UCL’s Saint-Luc University Hospitals, and Miikka Vikkula, a researcher at UCL’s de Duve Institute, have been studying angiomas in pursuit of a viable treatment.

To the general public the most well-known angioma is the birthmark, though it’s far from being the only kind. ‘The term refers more broadly to an anomaly (a tumour or deformity) of the blood vessels (capillaries, veins, arteries) or lymphatic vessels’, says Prof. Miikka Vikkula, a researcher at the de Duve Institute’s Human Molecular Genetics Laboratory. ‘Angiomas aren’t necessarily visible’, adds Dr Laurence Boon, coordinator of Centre for Vascular Anomalies of UCL’s Saint-Luc University Hospitals. ‘They can exist in almost any tissue that contains blood or lymphatic vessels: skin, muscle, mucous membrane, lung, brain.’ While an angioma often causes pain and/or bleeding, it can also cause other symptoms. ‘Everything depends on where it is’, says Prof. Vikkula. ‘Around the trachea, it’ll cause respiratory disorders. In the brain, neurological disorders. In the eye, vision problems.’ In short, patients can see their quality of life decline drastically owing to vascular malformation.

Angioma causes and origins

Angiomas are difficult to treat. Surgery and sclerotherapy help only some patients. Over two decades, Dr Boon and Prof. Vikkula have tried to understand the origin (probably genetic) of such vascular malformations. They concentrated on endothelial cells, which line the interior walls of blood vessels. A cell isn’t a tiny hermetically sealed sphere; it can capture external signals (from, for example, neighbouring cells) and draw them inside, especially via tiny doors that function like traffic lights: receptors. ‘We learned that 60% of vein malformations are caused by a genetic mutation on one of these receptors, called TIE2’,¹ explains Prof. Vikkula. ‘The mutated TIE2 constantly sends signals to the interior of the cell…even when there is no external signal telling it to do so. It’s like a traffic light that’s always green and lets by too many cars, or a loose tap that runs constantly. This congests the cell and especially disturbs one of its proteins, mTOR, which starts to act overzealously.’ mTOR regulates cellular growth, proliferation and differentiation. All of its functions thus disturbed, it disrupts those endothelial cells carrying the genetic mutation. Result: blood vessels fatten, multiply, and assume strange shapes. This is venous malformation.

                                          Rapamycine

A venous malformation drug

The good news: rapamycin can inhibit mTOR and force it to function normally. The drug is typically used to prevent post-transplant organ rejection and until recently had never been used to treat angiomas. After several laboratory experiments, Dr Boon was able to test it on a dozen of her patients—a world first, and the results were conclusive. Indeed, rapamycin:

• reduced lesion size by more than 15%;
• relieved pain significantly;
• stopped the bleeding suffered by some patients.

In light of this initial success, additional clinical trials have followed. In particular, a larger European study (approximately 250 patients) is being initiated to answer certain questions. Is rapamycin similarly effective against several forms of angiomas? Will it ultimately prevent new lesions? What happens when treatment stops? ‘This drug doesn’t cure the patient of angiomas, seeing as after four years of treatment the lesions didn’t disappear’, explains Dr Boon. ‘However, for patients who didn’t respond to conventional treatments, the difference is night and day! They all saw their quality of life improve, sometimes in spectacular fashion!’

That’s a source of hope for those who suffer from venous angiomas.

Candice Leblanc

(1) In 20% of cases, the genetic mutation is on PIK3CA, another molecule that travels the route along which TIE2 information is carried to mTOR. The consequences on and in the endothelial cell are nonetheless the same.

The research of Dr Boon and Prof. Vikkula has been funded primarily by the FNRS, ARC, PAI, NIH (US), de Duve Institute, Télévie grants, WELBIO and several awards.

A glance at Laurence Boon's bio

Coup d'oeil sur la bio de Miikka Vikkula