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Targeted therapy in patients with PIK3CA-related overgrowth syndrome

2018; Nature Portfolio; Volume: 558; Issue: 7711 Linguagem: Inglês

10.1038/s41586-018-0217-9

1476-4687

Quitterie Venot, Thomas Blanc, S. Hadj‐Rabia, Laureline Berteloot, Sophia Ladraa, Jean–Paul Duong Van Huyen, Estelle Blanc, Simon C. Johnson, Clément Hoguin, O. Boccara, Sabine Sarnacki, Nathalie Boddaert, Stéphanie Pannier, Frank Martinez, Sato Magassa, Junna Yamaguchi, Bertrand Knebelmann, Pierre Merville, Nicolas Grenier, Dominique Joly, Valérie Cormier‐Daire, Caroline Michot, Christine Bole‐Feysot, A. Picard, V. Soupre, Stanislas Lyonnet, Jérémy Sadoine, Lotfi Slimani, Catherine Chaussain, Cécile Laroche-Raynaud, Laurent Guibaud, Christine Broissand, Jeanne Amiel, Christophe Legendre, Fabiola Terzi, Guillaume Canaud,

Oral and gingival health research

CLOVES syndrome (congenital lipomatous overgrowth, vascular malformations, epidermal naevi, scoliosis/skeletal and spinal syndrome) is a genetic disorder that results from somatic, mosaic gain-of-function mutations of the PIK3CA gene, and belongs to the spectrum of PIK3CA-related overgrowth syndromes (PROS). This rare condition has no specific treatment and a poor survival rate. Here, we describe a postnatal mouse model of PROS/CLOVES that partially recapitulates the human disease, and demonstrate the efficacy of BYL719, an inhibitor of PIK3CA, in preventing and improving organ dysfunction. On the basis of these results, we used BYL719 to treat nineteen patients with PROS. The drug improved the disease symptoms in all patients. Previously intractable vascular tumours became smaller, congestive heart failure was improved, hemihypertrophy was reduced, and scoliosis was attenuated. The treatment was not associated with any substantial side effects. In conclusion, this study provides the first direct evidence supporting PIK3CA inhibition as a promising therapeutic strategy in patients with PROS.