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| Home > Articles > Published articles > The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib |
| Home > Articles > Published articles > The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib |
(Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Uppsala University) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Universitat Pompeu Fabra) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Hospital Sant Joan de Déu (Barcelona, Catalunya)) (Hospital Sant Joan de Déu (Barcelona, Catalunya)) (Institut Germans Trias i Pujol. Institut de Recerca contra la Leucèmia Josep Carreras) (Centro de Investigación Biomédica en Red de Cáncer)| Date: | 2022 |
| Abstract: | 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 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. |
| Grants: | "la Caixa" Foundation LCF/BQ/PR20/11770002 European Commission 749731 European Commission 675392 Agencia Estatal de Investigación SAF2017-89116-R Agencia Estatal de Investigación PID2020-116184RB-I00 Instituto de Salud Carlos III PI20/00102 "la Caixa" Foundation LCF/PR/HR19/52160023 "la Caixa" Foundation LCF/PR/PR16/51110035 |
| Note: | Asociación Española contra el Cáncer (GCTRA18006CARR) |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Published in: | EMBO Molecular Medicine, Vol. 14 Núm. 7 (july 2022) , p. e15619, ISSN 1757-4684 |
