Targeted therapy for capillary-venous malformations  

作　　者：Lola Zerbib Sophia Ladraa Antoine Fraissenon Charles Bayard Marina Firpion Quitterie Venot Sanela Protic Clément Hoguin Amandine Thomas Sylvie Fraitag Jean-Paul Duong Sophie Kaltenbach Estelle Balducci Coline Lefevre Patrick Villarese Vahid Asnafi Christine Broissand Nicolas Goudin Ivan Nemazanyy Gwennhael Autret Bertrand Tavitian Christophe Legendre Nadia Arzouk Veronique Minard-Colin Caroline Chopinet Michael Dussiot Denise MAdams Tristan Mirault Laurent Guibaud Paul Isenring Guillaume Canaud 

机构地区：[1]UniversitéParis Cité,Paris,France [2]INSERM U1151,Institut Necker-Enfants Malades,Paris,France [3]Service d’Imagerie Pédiatrique,Hôpital Femme-Mère-Enfant,HCL,Bron,France [4]CREATIS UMR 5220,Villeurbanne 69100,France [5]Service de Radiologie Mère-Enfant,Hôpital Nord,Saint Etienne,France [6]Service d’Anatomie pathologique,Hôpital Necker-Enfants Malades,AP-HP,Paris,France [7]Laboratoire d’Oncohématologie,Hôpital Necker-Enfants Malades,AP-HP,Paris,France [8]Pharmacie,Hôpital Necker-Enfants Malades,AP-HP,Paris,France [9]Necker Bio-Image Analysis,INSERM US24/CNRS UMS 3633,Paris,France [10]Platform for Metabolic Analyses,Structure Fédérative de Recherche Necker,INSERM US24/CNRS UMS 3633,Paris,France [11]Plateforme Imageries du Vivant,Universitéde Paris,PARCC,INSERM,Paris,France [12]Service de Néphrologie,Transplantation Adultes,Hôpital Necker-Enfants Malades,AP-HP,Paris,France [13]Service de Transplantation,Hôpital La PitiéSalpétrière,AP-HP,Paris,France [14]Department of Pediatric and Adolescent Oncology,INSERM 1015,Gustave Roussy,UniversitéParis-Saclay,Villejuif,France [15]Service de Physiologie&Explorations Fonctionnelles Cardiovasculaires,CHU de Lille,Lille 59000,France [16]INSERM U1163,Laboratory of Cellular and Molecular Mechanisms of Hematological Disorders and Therapeutic Implications,Laboratoire d’Excellence GR-Ex,Paris,France [17]Division of Oncology,Comprehensive Vascular Anomalies Program,Children’s Hospital of Philadelphia,Philadelphia,PA,USA [18]Service de Médecine Vasculaire,hôpital Européen Georges-Pompidou,Paris,France [19]Nephrology Research Group,L’Hôtel-Dieu de Québec Research Center,Department of Medicine,Faculty of Medicine,Laval University,Quebec,QC G1R2J6,Canada [20]Unitéde médecine translationnelle et thérapies ciblées,Hôpital Necker-Enfants Malades,AP-HP,Paris,France [21]CNRS UMR8253,Institut Necker-Enfants Malades,Paris,France

出　　处：《Signal Transduction and Targeted Therapy》2024年第7期3024-3039,共16页信号转导与靶向治疗（英文）

基　　金：supported by the European Research Council(CoG 2020 grant number 101000948 awarded to GC);the Agence Nationale de la Recherche-Programme d’Investissements d’Avenir(ANR-18-RHUS-005 to GC);the Agence Nationale de la Recherche-Programme de Recherche Collaborative(19-CE14-0030-01 to GC);supported by the CLOVES SYNDROME COMMUNITY(West Kennebunk,USA),Association Syndrome de CLOVES(Nantes,France),Fondation d’entreprise IRCEM(Roubaix,France),Fonds de dotation Emmanuel BOUSSARD(Paris,France),the Fondation DAY SOLVAY(Paris,France),the Fondation TOURRE(Paris,France)to GC,the Fondation BETTENCOURT SCHUELLER(Paris,France)to GC,the Fondation Simone et Cino DEL DUCA(Paris,France),the Fondation Line RENAUD-Loulou GASTE(Paris,France,the Fondation Schlumberger pour l’Education et la Recherche(Paris,France),the Association Robert Debrépour la Recherche.

摘　　要：Sporadic venous malformations are genetic conditions primarily caused by somatic gain-of-function mutation of PIK3CA or TEK,an endothelial transmembrane receptor signaling through PIK3CA.Venous malformations are associated with pain,bleedings,thrombosis,pulmonary embolism,esthetic deformities and,in severe cases,life-threatening situations.No authorized medical treatment exists for patients with venous malformations.Here,we created a genetic mouse model of PIK3CA-related capillary venous malformations that replicates patient phenotypes.We showed that these malformations only partially signal through AKT proteins.We compared the efficacy of different drugs,including rapamycin,a mTORC1 inhibitor,miransertib,an AKT inhibitor and alpelisib,a PI3Kαinhibitor at improving the lesions seen in the mouse model.We demonstrated the effectiveness of alpelisib in preventing vascular malformations’occurrence,improving the already established ones,and prolonging survival.Considering these findings,we were authorized to treat 25 patients with alpelisib,including 7 children displaying PIK3CA(n=16)or TEK(n=9)-related capillary venous malformations resistant to usual therapies including sirolimus,debulking surgical procedures or percutaneous sclerotherapies.We assessed the volume of vascular malformations using magnetic resonance imaging(MRI)for each patient.Alpelisib demonstrated improvement in all 25 patients.Vascular malformations previously considered intractable were reduced and clinical symptoms were attenuated.MRI showed a decrease of 33.4%and 27.8%in the median volume of PIK3CA and TEK malformations respectively,over 6 months on alpelisib.In conclusion,this study supports PI3Kαinhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

关 键 词：PIK3CA MALFORMATIONS VENOUS 

分 类 号：R394[医药卫生—医学遗传学]