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.
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This project received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program grants, (STG-2015) 679254 and (PoC-2016) 737546 (both awarded to G.C.). This work was also supported by the Emmanuel BOUSSARD Foundation, the DAY SOLVAY Foundation, Fondation TOURRE, Fondation Simone et Cino Del Duca, INSERM, Assistance Publique—Hôpitaux de Paris and the University of Paris, Descartes. We would like to thank the two patients and their families. We also thank C. Semaille from the ANSM for help and advice; S. Bisot-Locard (Novartis) for the BYL719; G. Autret for performing the mouse MRIs; S. Berissi and colleagues at the Plateforme d’histologie et morphologie du petit animal, INEM, Paris; S. Principe for administrative management; A. Klippel for advice and for providing plasmids encoding Myr-p110*-myc and Myr-p110*KR-myc constructs; K. Rajewsky for advice; and the radiological team from the Centre d’Imagerie de Franconville and in particular M. Canaud and A. Scemama for their help.
Nature thanks E. Baselga, W. Dobyns, R. Semple and B. Vanhaesebroeck for their contribution to the peer review of this work.