Université de Paris, Paris, 75006, France.
INSERM U1151, Institut Necker-Enfants Malades, Paris, 75015, France.
Sci Transl Med. 2021 Oct 6;13(614):eabg0809. doi: 10.1126/scitranslmed.abg0809.
Lymphatic cystic malformations are rare genetic disorders mainly due to somatic gain-of-function mutations in the 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 -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 -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 -related lymphatic anomalies.
淋巴管囊性畸形是一种罕见的遗传性疾病，主要是由于 基因的体细胞获得性功能突变引起的。这些异常常伴有疼痛、炎症发作、美容畸形，在严重的情况下，还会危及生命。目前，尚无针对淋巴管畸形患者的批准的医疗疗法。在这项概念验证研究中，我们开发了一种与 相关的淋巴管畸形的遗传小鼠模型，该模型重现了人类疾病。利用该模型，我们证明了 alpelisib（一种已批准的用于肿瘤学的 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疗效。基于这些结果，我们用 alpelisib 治疗了 6 名患有严重 相关淋巴管畸形的患者，其中包括 3 名儿童。这些患者已经接受了雷帕霉素、经皮硬化治疗和减瘤手术等治疗，但均未成功。我们使用磁共振成像（MRI）评估每位患者的淋巴管畸形体积。alpelisib 治疗后，6 名患者的病情均有改善。先前难以治疗的血管畸形缩小，疼痛和炎症发作减轻。在 alpelisib 治疗的 6 个月期间，MRI 显示淋巴管畸形的中位数体积减少了 48%。在研究期间，有 2 名患者出现了可能与 alpelisib 相关的不良反应，包括 1 级粘膜炎和腹泻。总之，这项研究支持 PIK3CA 抑制作为治疗 相关淋巴管异常患者的一种有前途的治疗策略。
