New and Emerging Targeted Therapies for Vascular Malformations

An Van Damme; Emmanuel Seront; Valérie Dekeuleneer; Laurence M. Boon; Miikka Vikkula

Disclosures

Am J Clin Dermatol. 2020;21(5):657-668. 

In This Article

Abstract and Introduction

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.

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 Mulliken and Glowacki.[1] The International Society for the Study of Vascular Anomalies has updated and extended this classification since 1996 and published the current extended version in 2015.[2] The classification was further updated in 2018 to include the most current information and is published on the International Society for the Study of Vascular Anomalies website (https://www.issva.org).[3]

The basis of this classification is the division of vascular anomalies into vascular tumors and vascular malformations. Vascular tumors are characterized by the abnormal proliferation of endothelial cells and blood vessels. They are subclassified as benign, locally aggressive, borderline, and malignant tumors.[2] Vascular malformations are inborn errors of vascular morphogenesis and consist of networks of abnormal blood and/or lymphatic vessels with weak endothelial cell proliferation. The recent update of this classification includes genetic knowledge that has rapidly accumulated during the past 10–20 years. In parallel, targeted molecular therapies have started to emerge.

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