New and Emerging Targeted Therapies for Vascular Malformations

Vascular malformations are inborn errors of vascular morphogenesis and consist of localized networks of abnormal blood and/or lymphatic vessels with weak endothelial cell proliferation. They have historically been managed by surgery and sclerotherapy. Extensive insight into the genetic origin and molecular mechanism of development has been accumulated over the last 20 years. Since the discovery of the first somatic mutations in a vascular anomaly 10 years ago, it is now recognized that they are perhaps all caused by inherited or somatic mutations in genes that hyperactivate two major intracellular signaling pathways: the RAS/MAPK/ERK and/or the phosphatidylinositol 3 kinase (PIK3)/protein kinase B/mammalian target of rapamycin (mTOR) pathway. Several targeted molecular inhibitors of these pathways have been developed, mostly for the treatment of cancers that harbor mutations in the same pathways. The mTOR inhibitor sirolimus is the most studied compound for the treatment of venous, lymphatic, and complex malformations. Disease responses of vascular malformations to sirolimus have now been reported in several studies in terms of clinical changes, quality of life, functional and radiological outcomes, and safety. Other targeted treatment strategies, such as the PIK3CA inhibitor alpelisib for PIK3CA-mutated vascular malformations, are also emerging. Repurposing of cancer drugs has become a major focus in this rapidly evolving field.