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 PI3Kα inhibitor 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 PI3Kα inhibition as a promising therapeutic strategy in patients with PIK3CA or TEK-related capillary venous malformations.

散发性静脉畸形是主要由PIK3CA或TEK（一种通过 PIK3CA 传递信号的内皮跨膜受体）体细胞功能获得性突变引起的遗传性疾病。静脉畸形与疼痛、出血、血栓形成、肺栓塞、审美畸形有关，严重时甚至会危及生命。对于静脉畸形患者，尚无授权的治疗方法。在这里，我们创建了PIK3CA相关毛细血管静脉畸形的遗传小鼠模型，该模型复制了患者表型。我们发现这些畸形仅部分通过 AKT 蛋白发出信号。我们比较了不同药物的功效，包括雷帕霉素（一种 mTORC1 抑制剂）、miransertib（一种 AKT 抑制剂）和 alpelisib（一种 PI3Kα 抑制剂）在改善小鼠模型中所见病变方面的功效。我们证明了alpelisib在预防血管畸形的发生、改善已形成的血管畸形以及延长生存期方面的有效性。考虑到这些发现，我们被授权使用 alpelisib 治疗 25 名患者，其中包括 7 名表现出PIK3CA ( n = 16) 或TEK ( n = 9) 相关毛细血管静脉畸形的儿童，这些儿童对西罗莫司、肿瘤减灭手术或经皮硬化疗法等常规疗法耐药。我们使用磁共振成像 (MRI) 评估了每位患者的血管畸形体积。 Alpelisib 在所有 25 名患者中均表现出改善。以前被认为难以治愈的血管畸形减少了，临床症状也减轻了。 MRI 显示，服用 alpelisib 6 个月后，PIK3CA 和 TEK 畸形的中位体积分别减少了 33.4% 和 27.8%。 总之，本研究支持 PI3Kα 抑制作为PIK3CA或TEK相关毛细血管静脉畸形患者的一种有前景的治疗策略。