Targeted therapy in patients with PIK3CA-related overgrowth syndrome

被引：405

作者：

Venot, Quitterie ^{[1
]}

Blanc, Thomas ^{[1
,2
,3
]}

Rabia, Smail Hadj ^{[2
,4
,5
]}

Berteloot, Laureline ^{[5
,6
]}

Ladraa, Sophia ^{[1
]}

Duong, Jean-Paul ^{[2
,7
]}

Blanc, Estelle ^{[8
]}

Johnson, Simon C. ^{[9
]}

Hoguin, Clement ^{[1
]}

Boccara, Olivia ^{[4
]}

Sarnacki, Sabine ^{[2
,3
]}

Boddaert, Nathalie ^{[2
,5
,6
]}

Pannier, Stephanie ^{[2
,10
]}

Martinez, Frank ^{[11
]}

Magassa, Sato ^{[1
]}

Yamaguchi, Junna ^{[1
]}

Knebelmann, Bertrand ^{[1
,2
,11
]}

Merville, Pierre ^{[12
,13
]}

Grenier, Nicolas ^{[14
]}

Joly, Dominique ^{[1
,2
,11
]}

Cormier-Daire, Valerie ^{[2
,5
,15
]}

Michot, Caroline ^{[2
,5
,15
]}

Bole-Feysot, Christine ^{[5
]}

Picard, Arnaud ^{[2
,16
]}

Soupre, Veronique ^{[16
]}

Lyonnet, Stanislas ^{[2
,5
,15
]}

Sadoine, Jeremy ^{[17
]}

Slimani, Lotfi ^{[17
]}

Chaussain, Catherine ^{[2
,17
]}

Laroche-Raynaud, Cecile ^{[18
]}

Guibaud, Laurent ^{[19
]}

Broissand, Christine ^{[20
]}

Amiel, Jeanne ^{[2
,5
,15
]}

Legendre, Christophe ^{[1
,2
]}

Terzi, Fabiola ^{[1
,2
]}

Canaud, Guillaume ^{[1
,2
,11
]}

机构：

[1] Inst Necker Enfants Malad, INSERM, U1151, Paris, France

[2] Univ Paris 05, Sorbonne Paris Cite, Paris, France

[3] Hop Necker Enfants Malad, AP HP, Serv Chirurg Viscerale Pediat, Paris, France

[4] Hop Necker Enfants Malad, AP HP, Serv Dermatol Pediat, Paris, France

[5] Hop Necker Enfants Malad, AP HP, Inst Imagine, UMR 1163, Paris, France

[6] Hop Necker Enfants Malad, AP HP, Dept Radiol Pediat, Paris, France

[7] Hop Necker Enfants Malad, AP HP, Dept Anatomopathol, Paris, France

[8] Hop Marie Lannelongue, Dept Nucl Med, Le Plessis Robinsson, France

[9] Seattle Childrens Res Inst, Dept Integrat Brain Res, Seattle, WA USA

[10] Hop Necker Enfants Malad, AP HP, Serv Orthoped Pediat, Paris, France

[11] Hop Necker Enfants Malad, AP HP, Serv Nephrol Transplantat Adultes, Paris, France

[12] CHU Pellegrin, Serv Nephrol, Transplantat, Dialyse,Aphereses, Bordeaux, France

[13] CNRS, Immuno ConcEpT, UMR 5164, Bordeaux, France

[14] CHU Pellegrin, Serv Imagerie Diagnost & Intervent Adulte, Bordeaux, France

[15] Hop Necker Enfants Malad, AP HP, Serv Genet Med, Paris, France

[16] Hop Necker Enfants Malad, AP HP, Serv Chirurg Maxillofaciale & Chirurg Plast, Paris, France

[17] Lab EA 2496 Orofacial Pathol Imaging & Biotherapi, Montrouge, France

[18] Hop Mere & Enfant, Serv Neuropediat, Limoges, France

[19] Hop Femme Mere Enfant, Serv Imagerie Pediat, Bron, France

[20] Hop Necker Enfants Malad, AP HP, Pharm, Paris, France

来源：

NATURE | 2018年 / 558卷 / 7711期

基金：

欧洲研究理事会;

关键词：

PHOSPHATIDYLINOSITOL; 3-KINASE; PIK3CA(H1047R) MUTATION; EXPRESSION; INHIBITION; NVP-BYL719; DISCOVERY; SPECTRUM; CRITERIA;

D O I：

10.1038/s41586-018-0217-9

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：540 / +

页数：29

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