Académie royale de Médecine de Belgique

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Résumé de Mikka Vikkula, membre titulaire

(A pris part à la discussion : le Pr K. Alitalo).

MOLECULAR MECHANISMS BEHIND LYMPHATIC AND VASCULAR ANOMALIES : NOVEL TARGETS FOR THERAPY ?

par Miikka VIKKULA (UCL – Institut de Duve), membre titulaire.

Lymphatic and vascular anomalies are developmental defects implicating lymph/angiogenesis. Malformations of the lymphatic and vascular vessels are localized lesions, creating painful masses of malformed vessels mixed with extracellular matrix and interstitial cells. Genetic studies demonstrated that they are most commonly caused by somatic genetic defects in lymph/vascular endothelial cells. Usually a mutation is identified in the catalytic subunit of the phosphoinositol-3-kinase (PI3K). These hot-spot mutations are shared with various cancers, and they cause chronic activation of PI3K. Using cells carrying such a mutation, we generated the first model for venous malformations, and used it in a preclinical trial to test the effects of some inhibitors. The positive effects prompted us to move towards a clinical pilot study, which underscored promising outcomes. Therefore, a larger phase III trial was set-up, and it is currently running in Cliniques Saint-Luc.

Lymphedema is another type of lymphatic anomaly, caused by dysfunction of the lymphatic system. It consists of chronic disabling swelling that mostly occurs on the lower extremities. It can be primary (congenital) or secondary (acquired). Familial primary lymphedema can be inherited as an autosomal dominant or recessive disease. It can also occur in a syndromic form, combined with other clinical features. Over the years, more than 20 genes that can be mutated in different isolated or syndromic forms of lymphedema have been identified. They explain about 40-50% of the inherited forms. It seems that the majority of these genes, and especially the functions of the encoded proteins, are somehow involved in the signaling pathway of the major lymphatic regulator, vascular endothelial growth factor C, and its receptor VEGFR3. This underscores the important role that this pathway plays in lymphatic development and function, and suggests that the yet unknown genes may also have a role in the same pathway. It also pinpoints this pathway for development of future therapies for primary lymphedema.