Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the PIK3CA gene. These anomalies are frequently associated with pain, inflammatory flares, esthetic deformities, and, in severe forms, life-threatening conditions. There is no approved medical therapy for patients with lymphatic malformations. In this proof-of-concept study, we developed a genetic mouse model of PIK3CA-related lymphatic malformations that recapitulates human disease. Using this model, we demonstrated the efficacy of alpelisib, an approved pharmacological inhibitor of PIK3CA in oncology, in preventing lymphatic malformation occurrence, improving lymphatic anomalies, and extending survival. On the basis of these results, we treated six patients with alpelisib, including three children, displaying severe PIK3CA-related lymphatic malformations. Patients were already unsuccessfully treated with rapamycin, percutaneous sclerotherapies, and debulking surgical procedures. We assessed the volume of lymphatic malformations using magnetic resonance imaging (MRI) for each patient. Alpelisib administration was associated with improvements in the six patients. Previously intractable vascular malformations shrank, and pain and inflammatory flares were attenuated. MRI showed a decrease of 48% in the median volume of lymphatic malformations over 6 months on alpelisib. During the study, two patients developed adverse events potentially related to alpelisib, including grade 1 mucositis and diarrhea. In conclusion, this study supports PIK3CA inhibition as a promising therapeutic strategy in patients with PIK3CA-related lymphatic anomalies.

中文翻译：

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Alpelisib 给药可减少小鼠模型和患者的淋巴畸形


淋巴囊性畸形是一种罕见的遗传性疾病，主要是由于PIK3CA基因的体细胞功能获得性突变所致。这些异常通常与疼痛、炎症发作、审美畸形有关，严重时甚至会危及生命。对于淋巴管畸形患者，尚无批准的药物治疗方法。在这项概念验证研究中，我们开发了一种PIK3CA相关淋巴管畸形的遗传小鼠模型，该模型概括了人类疾病。使用该模型，我们证明了 alpelisib（一种在肿瘤学中已批准的 PIK3CA 药理学抑制剂）在预防淋巴管畸形发生、改善淋巴管异常和延长生存期方面的功效。根据这些结果，我们用 alpelisib 治疗了 6 名患者，其中包括 3 名儿童，表现出严重的PIK3CA相关淋巴管畸形。患者已经接受过雷帕霉素、经皮硬化疗法和减瘤手术治疗，但均未成功。我们使用磁共振成像 (MRI) 评估了每位患者的淋巴畸形体积。 Alpelisib 给药与六名患者的改善有关。以前顽固的血管畸形缩小了，疼痛和炎症也减轻了。 MRI 显示，服用 alpelisib 6 个月后，淋巴管畸形的中位体积减少了 48%。研究期间，两名患者出现了可能与 alpelisib 相关的不良事件，包括 1 级粘膜炎和腹泻。总之，本研究支持 PIK3CA 抑制作为PIK3CA相关淋巴异常患者的一种有前景的治疗策略。