Targeted therapy in patients with PIK3CA-related overgrowth syndrome

被引:398
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
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
收藏
页码:540 / +
页数:29
相关论文
共 27 条
[1]  
Canaud G, 2014, NEW ENGL J MED, V371, P1554, DOI [10.1056/NEJMoa1312890, 10.1056/NEJMc1410247]
[2]   AKT2 is essential to maintain podocyte viability and function during chronic kidney disease [J].
Canaud, Guillaume ;
Bienaime, Frank ;
Viau, Amandine ;
Treins, Caroline ;
Baron, William ;
Nguyen, Clement ;
Burtin, Martine ;
Berissi, Sophie ;
Giannakakis, Konstantinos ;
Muda, Andrea Onetti ;
Zschiedrich, Stefan ;
Huber, Tobias B. ;
Friedlander, Gerard ;
Legendre, Christophe ;
Pontoglio, Marco ;
Pende, Mario ;
Terzi, Fabiola .
NATURE MEDICINE, 2013, 19 (10) :1288-+
[3]   Somatic activating mutations in Pik3ca cause sporadic venous malformations in mice and humans [J].
Castillo, Sandra D. ;
Tzouanacou, Elena ;
Zaw-Thin, May ;
Berenjeno, Inma M. ;
Parker, Victoria E. R. ;
Chivite, Inigo ;
Mila-Guasch, Maria ;
Pearce, Wayne ;
Solomon, Isabelle ;
Angulo-Urarte, Ana ;
Figueiredo, Ana M. ;
Dewhurst, Robert E. ;
Knox, Rachel G. ;
Clark, Graeme R. ;
Scudamore, Cheryl L. ;
Badar, Adam ;
Kalber, Tammy L. ;
Foster, Julie ;
Stuckey, Daniel J. ;
David, Anna L. ;
Phillips, Wayne A. ;
Lythgoe, Mark F. ;
Wilson, Valerie ;
Semple, Robert K. ;
Sebire, Neil J. ;
Kinsler, Veronica A. ;
Graupera, Mariona ;
Vanhaesebroeck, Bart .
SCIENCE TRANSLATIONAL MEDICINE, 2016, 8 (332)
[4]   Targeting PI3K signalling in cancer: opportunities, challenges and limitations [J].
Engelman, Jeffrey A. .
NATURE REVIEWS CANCER, 2009, 9 (08) :550-562
[5]   Characterization of the Novel and Specific PI3Kα Inhibitor NVP-BYL719 and Development of the Patient Stratification Strategy for Clinical Trials [J].
Fritsch, Christine ;
Huang, Alan ;
Chatenay-Rivauday, Christian ;
Schnell, Christian ;
Reddy, Anupama ;
Liu, Manway ;
Kauffmann, Audrey ;
Guthy, Daniel ;
Erdmann, Dirk ;
De Pover, Alain ;
Furet, Pascal ;
Gao, Hui ;
Ferretti, Stephane ;
Wang, Youzhen ;
Trappe, Joerg ;
Brachmann, Saskia M. ;
Maira, Sauveur-Michel ;
Wilson, Christopher ;
Boehm, Markus ;
Garcia-Echeverria, Carlos ;
Chene, Patrick ;
Wiesmann, Marion ;
Cozens, Robert ;
Lehar, Joseph ;
Schlegel, Robert ;
Caravatti, Giorgio ;
Hofmann, Francesco ;
Sellers, William R. .
MOLECULAR CANCER THERAPEUTICS, 2014, 13 (05) :1117-1129
[6]   Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation [J].
Furet, Pascal ;
Guagnano, Vito ;
Fairhurst, Robin A. ;
Imbach-Weese, Patricia ;
Bruce, Ian ;
Knapp, Mark ;
Fritsch, Christine ;
Blasco, Francesca ;
Blanz, Joachim ;
Aichholz, Reiner ;
Hamon, Jacques ;
Fabbro, Doriano ;
Caravatti, Giorgio .
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (13) :3741-3748
[7]   Sirolimus for the Treatment of Complicated Vascular Anomalies in Children [J].
Hammill, Adrienne M. ;
Wentzel, MarySue ;
Gupta, Anita ;
Nelson, Stephen ;
Lucky, Anne ;
Elluru, Ravi ;
Dasgupta, Roshni ;
Azizkhan, Richard G. ;
Adams, Denise M. .
PEDIATRIC BLOOD & CANCER, 2011, 57 (06) :1018-1024
[8]   Heterozygous expression of the oncogenic Pik3caH1047R mutation during murine development results in fatal embryonic and extraembryonic defects [J].
Hare, Lauren M. ;
Schwarz, Quenten ;
Wiszniak, Sophie ;
Gurung, Rajendra ;
Montgomery, Karen G. ;
Mitchell, Christina A. ;
Phillips, Wayne A. .
DEVELOPMENTAL BIOLOGY, 2015, 404 (01) :14-26
[9]   Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: A tool for temporally regulated gene activation/inactivation in the mouse [J].
Hayashi, S ;
McMahon, AP .
DEVELOPMENTAL BIOLOGY, 2002, 244 (02) :305-318
[10]   TARGETS FOR CELL-CYCLE ARREST BY THE IMMUNOSUPPRESSANT RAPAMYCIN IN YEAST [J].
HEITMAN, J ;
MOVVA, NR ;
HALL, MN .
SCIENCE, 1991, 253 (5022) :905-909