New and Emerging Targeted Therapies for Vascular Malformations
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REVIEW ARTICLE
New and Emerging Targeted Therapies for Vascular Malformations An Van Damme1,2 · Emmanuel Seront1,3 · Valérie Dekeuleneer1 · Laurence M. Boon1,4 · Miikka Vikkula1,4,5
© Springer Nature Switzerland AG 2020
Abstract 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.
1 Introduction Vascular anomalies are a heterogeneous group of disorders characterized by abnormal growth and/or development of lymphatic and/or blood vessels. They remain a diagnostic and therapeutic challenge and are associated with very diverse symptomatology and morphology. Diagnostic and therapeutic progress for these disorders has been greatly facilitated by the classification and terminology initiated by * Miikka Vikkula [email protected] 1
Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Centre, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium
2
Institut Roi Albert II, Department of Pediatric Hematology and Oncology, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium
3
Institut Roi Albert II, Department of Medical Oncology, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium
4
Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74, 1200 Brussels, Belgium
5
WELBIO (Walloon Excellence in Lifesciences and Biotechnology), de Duve Institute, University of Louvain, Brussels, Belgium
Key Points Molecular and pathophysiological understanding of vascular anomalies has been immensely improved in recent years, establishing that most are associated with mutations in the ph
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