The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib
Por:
Kobialka, P, Sabata, H, Vilalta, O, Gouveia, L, Angulo-Urarte, A, Muixi, L, Zanoncello, J, Munoz-Aznar, O, Olaciregui, NG, Fanlo, L, Esteve-Codina, A, Lavarino, C, Javierre, BM, Celis, V, Rovira, C, Lopez-Fernandez, S, Baselga, E, Mora, J, Castillo, SD, Graupera, M
Publicada:
7 jul 2022
Ahead of Print:
1 jun 2022
Resumen:
Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3ca(H1047R) activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K-driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low-flow vascular malformations.
Filiaciones:
Kobialka, P:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Sabata, H:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Vilalta, O:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Gouveia, L:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden
Angulo-Urarte, A:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Muixi, L:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Zanoncello, J:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Munoz-Aznar, O:
Inst Recerca St Joan de Deu, Dev Tumor Biol Lab, Barcelona, Spain
Olaciregui, NG:
Inst Recerca St Joan de Deu, Dev Tumor Biol Lab, Barcelona, Spain
Fanlo, L:
Josep Carreras Leukaemia Res Inst, 3D Chromatin Org, Barcelona, Spain
Esteve-Codina, A:
Barcelona Inst Sci & Technol, Ctr Genom Regulat, CNAG CRG, Barcelona, Spain
Univ Pompeu Fabra UPF, Barcelona, Spain
Lavarino, C:
Inst Recerca St Joan de Deu, Dev Tumor Biol Lab, Barcelona, Spain
Javierre, BM:
Josep Carreras Leukaemia Res Inst, 3D Chromatin Org, Barcelona, Spain
Celis, V:
Hosp St Joan de Deu Barcelona, Pediat Canc Ctr Barcelona, Barcelona, Spain
Rovira, C:
Hosp St Joan de Deu Barcelona, Dept Pathol, Barcelona, Spain
Lopez-Fernandez, S:
Hosp Santa Creu & Sant Pau, Dept Plast Surg, Barcelona, Spain
Baselga, E:
Hosp St Joan de Deu, Dept Dermatol, Barcelona, Spain
Mora, J:
Inst Recerca St Joan de Deu, Dev Tumor Biol Lab, Barcelona, Spain
Hosp St Joan de Deu Barcelona, Pediat Canc Ctr Barcelona, Barcelona, Spain
Castillo, SD:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Graupera, M:
Josep Carreras Leukaemia Res Inst, Endothelial Pathobiol & Microenvironm, Barcelona, Spain
Inst Salud Carlos III, CIBERONC, Madrid, Spain
Green Published, All Open Access; Green
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