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New and Emerging Targeted Therapies for Vascular Malformations

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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.

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Authors and Affiliations

  1. Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Centre, Saint Luc University Hospital, Avenue Hippocrate 10, 1200, Brussels, Belgium

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

  2. Institut Roi Albert II, Department of Pediatric Hematology and Oncology, Saint Luc University Hospital, Avenue Hippocrate 10, 1200, Brussels, Belgium

    An Van Damme

  3. Institut Roi Albert II, Department of Medical Oncology, Saint Luc University Hospital, Avenue Hippocrate 10, 1200, Brussels, Belgium

    Emmanuel Seront

  4. Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74, 1200, Brussels, Belgium

    Laurence M. Boon & Miikka Vikkula

  5. WELBIO (Walloon Excellence in Lifesciences and Biotechnology), de Duve Institute, University of Louvain, Brussels, Belgium

    Miikka Vikkula

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  1. An Van Damme
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  2. Emmanuel Seront
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Contributions

AVD performed the literature search and data analysis, and drafted the manuscript. ES, VD, LMB, and MV critically revised the work. The authors of this publication are members of the Vascular Anomalies Working Group (VASCA WG) of the European Reference Network for Rare Multisystemic Vascular Diseases (VASCERN), Project ID: 769036.

Corresponding author

Correspondence to Miikka Vikkula.

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No sources of funding were used to assist in the preparation of this review.

Conflict of interest

An Van Damme and Valérie Dekeuleneer have no conflicts of interest that are directly relevant to the content of this article. Emmanuel Seront discloses the following interactions with the medical industry: (1) clinical trial support for VASE: Pfizer [slow-flow vascular anomalies (rapamycin)] and (2) clinical trial support for TRAMAV: Novartis [fast-flow vascular anomalies (trametinib)]. Laurence M. Boon discloses the following interactions with the medical industry: (1) clinical trial support for VASE: Pfizer [slow-flow vascular anomalies (rapamycin)]; (2) clinical trial support for TRAMAV: Novartis [fast-flow vascular anomalies (trametinib)]; (3) clinical advisory board: Venthera [slow-flow malformations (transdermal PI3K inhibitor)]; and (4) clinical advisory board: Pierre Fabre [infantile hemangiomas (beta-blockers)]. Miikka Vikkula discloses the following interactions with the medical industry: (1) research grant from Deciphera Pharmaceuticals [venous malformations (rebastinib)] and (2) scientific and clinical advisory boards: Venthera [slow-flow malformations (transdermal PI3K inhibitor)].

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Van Damme, A., Seront, E., Dekeuleneer, V. et al. New and Emerging Targeted Therapies for Vascular Malformations. Am J Clin Dermatol 21, 657–668 (2020). https://doi.org/10.1007/s40257-020-00528-w

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