Targeted therapy for capillary-venous malformations

Sporadic venous malformations are genetic conditions primarily driven by somatic gain-of-function mutations in PIK3CA or in TEK, an endothelial transmembrane receptor that signals through PIK3CA. These malformations are associated with pain, bleeding, thrombosis, pulmonary embolism, aesthetic deformities, and, in severe cases, life-threatening complications. Currently, no approved medical treatments exist for patients with venous malformations.

In this study, we developed a genetic mouse model of PIK3CA-related capillary venous malformations that closely replicates the phenotypes observed in patients. We found that these malformations signal only partially through AKT proteins. To identify effective therapeutic options, we evaluated the efficacy of several drugs, including rapamycin, an mTORC1 inhibitor; miransertib, an AKT inhibitor; and alpelisib, a PI3Kα inhibitor, in improving the lesions observed in our mouse model. Our results demonstrated that alpelisib effectively prevented the formation of vascular malformations, improved existing lesions, and extended survival in the model.

Based on these preclinical findings, we received authorization to treat 25 patients, including 7 children, with alpelisib. These patients had PIK3CA- (n = 16) or TEK- (n = 9) related capillary venous malformations that were resistant to standard therapies such as sirolimus, debulking surgeries, or percutaneous sclerotherapies. We monitored the volume of vascular malformations in each patient using magnetic resonance imaging (MRI). Treatment with alpelisib led to improvements in all 25 patients, reducing previously intractable malformations and alleviating clinical symptoms. MRI assessments revealed a median volume reduction of 33.4% in PIK3CA-related malformations and 27.8% in TEK-related malformations over six months of treatment.

In conclusion, this study supports the use of PI3Kα inhibition as a promising therapeutic strategy for patients with PIK3CA- or TEK-related capillary venous malformations.