Journal Article

Targeted therapy for capillary-venous malformations

Nemazanyy, Ivan, Chopinet, Caroline, Duong, Jean-Paul, Mirault, Tristan, Balducci, Estelle, Goudin, Nicolas, Hoguin, Clément, Minard-Colin, Veronique, Broissand, Christine, Firpion, Marina, Tavitian, Bertrand, Dussiot, Michael, Fraitag, Sylvie, Protic, Sanela, Isenring, Paul, Adams, Denise M., Kaltenbach, Sophie, Thomas, Amandine, Lefevre, Coline, Ladraa, Sophia, Villarese, Patrick, Guibaud, Laurent, Zerbib, Lola, Legendre, Christophe, Fraissenon, Antoine, Bayard, Charles, Autret, Gwennhael, Arzouk, Nadia, Venot, Quitterie, Asnafi, Vahid, Canaud, Guillaume

2024

Overview

Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK , an endothelial transmembrane receptor signaling through PIK3CA. Venous malformations are associated with pain, bleedings, thrombosis, pulmonary embolism, esthetic deformities and, in severe cases, life-threatening situations. No authorized medical treatment exists for patients with venous malformations. Here, we created a genetic mouse model of PIK3CA -related capillary venous malformations that replicates patient phenotypes. We showed that these malformations only partially signal through AKT proteins. We compared the efficacy of different drugs, including rapamycin, a mTORC1 inhibitor, miransertib, an AKT inhibitor and alpelisib, a PI3Kα inhibitor at improving the lesions seen in the mouse model. We demonstrated the effectiveness of alpelisib in preventing vascular malformations’ occurrence, improving the already established ones, and prolonging survival. Considering these findings, we were authorized to treat 25 patients with alpelisib, including 7 children displaying PIK3CA ( n  = 16) or TEK ( n  = 9)-related capillary venous malformations resistant to usual therapies including sirolimus, debulking surgical procedures or percutaneous sclerotherapies. We assessed the volume of vascular malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib demonstrated improvement in all 25 patients. Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated. MRI showed a decrease of 33.4% and 27.8% in the median volume of PIK3CA and TEK malformations respectively, over 6 months on alpelisib. In conclusion, this study supports PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK -related capillary venous malformations.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/208/1516 / 692/308/575 / AKT protein / Animals / Cancer Research / Capillaries - drug effects / Capillaries - pathology / Cell Biology / Cell surface receptors / Child / Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors / Class I Phosphatidylinositol 3-Kinases - genetics / Disease Models, Animal / Embolism / Female / Humans / Internal Medicine / Magnetic resonance imaging / Male / Medical treatment / Medicine / Medicine & Public Health / Mice / Molecular Targeted Therapy / Oncology / Pathology / Patients / Phenotypes / Rapamycin / Sirolimus - pharmacology / Sirolimus - therapeutic use / Thiazoles / Thrombosis / Vascular Malformations - drug therapy / Vascular Malformations - genetics / Vascular Malformations - pathology