New and Emerging Targeted Therapies for Vascular Malformations

NI not indicated, PJP pneumocystis jirovecii prophylaxis, q12h every 12 hours

AED anti-epileptic drugs, Ca carcinoma, CNI calcineurin inhibitor, CS corticosteroid, KHE Kaposiform hemangio-endothelioma, KMP Kassabach Merrit phenomenon, MMF mycophenolate mofetil, NI not indicated, PJP pneumocystis jirovecii prophylaxis, RCT randomized controlled trial, SOT solid organ transplantation, TSC tuberous sclerosis complex, Tx transplantation, VCR vincristine

Authors and Disclosures

An Van Damme^1,2, Emmanuel Seront^1,3, Valérie Dekeuleneer¹, Laurence M. Boon^1,4 and Miikka Vikkula<sup>1,4,5

1</sup>Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Centre, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium miikka.vikkula@uclouvain.be
²Institut Roi Albert II, Department of Pediatric Hematology and Oncology, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium
³Institut Roi Albert II, Department of Medical Oncology, Saint Luc University Hospital, Avenue Hippocrate 10, 1200 Brussels, Belgium
⁴Human Molecular Genetics, de Duve Institute, University of Louvain, Avenue Hippocrate 74, 1200 Brussels, Belgium miikka.vikkula@uclouvain.be
⁵WELBIO (Walloon Excellence in Lifesciences and Biotechnology), de Duve Institute, University of Louvain, Brussels, Belgium miikka.vikkula@uclouvain.be

Author 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.

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)].

Sidebar

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 phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin (mTOR) or the RAS/MAPK/ERK pathway.

Several targeted compounds exist, and some are being planned to be used, or are being tested off-label to directly impact the appearance and symptomatology of these lesions.

Sirolimus, a direct mTOR inhibitor, has been the most extensively tested so far, including prospective clinical trials, yet other targeted inhibitors of these pathways are emerging as potential treatments for vascular malformations.