Targeted therapy in patients with PIK3CA-related overgrowth syndrome

Quitterie Venot, Thomas Blanc, Smail Hadj Rabia, Laureline Berteloot, Sophia Ladraa, Jean-Paul Duong, Estelle Blanc, Simon C. Johnson, Clément Hoguin, Olivia Boccara, Sabine Sarnacki, Nathalie Boddaert, Stephanie Pannier, Frank Martinez, Sato Magassa, Junna Yamaguchi, Bertrand Knebelmann, Pierre Merville, Nicolas Grenier, Dominique Joly, Valérie Cormier-Daire, Caroline Michot, Christine Bole-Feysot, Arnaud Picard, Véronique Soupre, Stanislas Lyonnet, Jeremy Sadoine, Lotfi Slimani, Catherine Chaussain, Cécile Laroche-Raynaud, Laurent Guibaud, Christine Broissand, Jeanne Amiel, Christophe Legendre, Fabiola Terzi and Guillaume Canaud ()
Additional contact information
Quitterie Venot: INSERM U1151, Institut Necker Enfants Malades
Thomas Blanc: INSERM U1151, Institut Necker Enfants Malades
Smail Hadj Rabia: Université Paris Descartes, Sorbonne Paris Cité
Laureline Berteloot: UMR-1163 Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP
Sophia Ladraa: INSERM U1151, Institut Necker Enfants Malades
Jean-Paul Duong: Université Paris Descartes, Sorbonne Paris Cité
Estelle Blanc: Hôpital Marie Lannelongue
Simon C. Johnson: Seattle Children’s Research Institute
Clément Hoguin: INSERM U1151, Institut Necker Enfants Malades
Olivia Boccara: Service de Dermatologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP
Sabine Sarnacki: Université Paris Descartes, Sorbonne Paris Cité
Nathalie Boddaert: Université Paris Descartes, Sorbonne Paris Cité
Stephanie Pannier: Université Paris Descartes, Sorbonne Paris Cité
Frank Martinez: Service de Néphrologie Transplantation Adultes, Hôpital Necker-Enfants Malades, AP-HP
Sato Magassa: INSERM U1151, Institut Necker Enfants Malades
Junna Yamaguchi: INSERM U1151, Institut Necker Enfants Malades
Bertrand Knebelmann: INSERM U1151, Institut Necker Enfants Malades
Pierre Merville: Service de Néphrologie, Transplantation, Dialyse, Aphérèses, Centre Hospitalier Universitaire Pellegrin
Nicolas Grenier: Service d’Imagerie Diagnostique et Interventionnelle de l’Adulte, Centre Hospitalier Universitaire Pellegrin
Dominique Joly: INSERM U1151, Institut Necker Enfants Malades
Valérie Cormier-Daire: Université Paris Descartes, Sorbonne Paris Cité
Caroline Michot: Université Paris Descartes, Sorbonne Paris Cité
Christine Bole-Feysot: UMR-1163 Institut Imagine, Hôpital Necker-Enfants Malades, AP-HP
Arnaud Picard: Université Paris Descartes, Sorbonne Paris Cité
Véronique Soupre: Service de Chirurgie Maxillo-faciale et Chirurgie Plastique, Hôpital Necker-Enfants Malades, AP-HP
Stanislas Lyonnet: Université Paris Descartes, Sorbonne Paris Cité
Jeremy Sadoine: Laboratory EA 2496 Orofacial Pathologies, Imaging and Biotherapies
Lotfi Slimani: Laboratory EA 2496 Orofacial Pathologies, Imaging and Biotherapies
Catherine Chaussain: Université Paris Descartes, Sorbonne Paris Cité
Cécile Laroche-Raynaud: Service de Neuropédiatrie, Hôpital de la Mère et de l’Enfant
Laurent Guibaud: Service d’Imagerie Pédiatrique, Hôpital Femme-Mère-Enfant
Christine Broissand: Pharmacie, Hôpital Necker-Enfants Malades, AP-HP
Jeanne Amiel: Université Paris Descartes, Sorbonne Paris Cité
Christophe Legendre: INSERM U1151, Institut Necker Enfants Malades
Fabiola Terzi: INSERM U1151, Institut Necker Enfants Malades
Guillaume Canaud: INSERM U1151, Institut Necker Enfants Malades

Nature, 2018, vol. 558, issue 7711, 540-546

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41586-018-0217-9

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