New and Emerging Targeted Therapies for Vascular Malformations

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


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

In This Article

Genetics and Pathophysiology

Extensive insight into the genetic and pathophysiologic origin of vascular anomalies is being accumulated. They are now mostly considered to be caused by abnormal signaling within vascular endothelial cells. This knowledge originates from the elucidation of the genetic anomalies behind some of the rare familial forms. Further studies demonstrated additional involvement of somatic tissue-specific mutations, which led to the hypothesis that a similar mechanism could be responsible for the more common sporadic cases. Moreover, understanding the dysfunctions caused by the mutations at the protein level has laid the basis for novel targeted therapies.[8,11–20,22]

Patients affected by the inherited forms typically have multifocal small lesions, which increase in number over time. They are transmitted in an autosomal dominant manner and phenotypic penetrance, age at onset, and severity vary among mutation carriers. These characteristics seem to be explained by involvement of a para-dominant mechanism, involving a secondary somatic mutation in the second allele of the same gene, thereby abolishing normal gene function completely.[11] This has since been proven for almost all the 11 known inherited vascular anomalies. The importance of somatic mutations in the occurrence of vascular anomalies led to the hypothesis that the more frequently occurring sporadic forms could be due to somatic changes alone. Similar to oncology, tumor suppressor genes usually need two hits that both lead to loss of function (one eventually germline, the other as somatic) whereas oncogenes "only" need a single activating hit. The first confirmation of this hypothesis was the demonstration that 60% of sporadic VMs have a somatic activating mutation in TIE2/TEK.[12,13]

It is now established that most vascular malformations are caused by somatic or mosaic mutations that activate at least one of the two major intracellular signaling pathways: the RAS/MAPK/ERK or the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway[14] (Figure 1).

Figure 1.

Intracellular signaling pathways involved in vascular malformations and targets for therapy. ANGPT-1 angiopoietin 1, AVM arteriovenous malformation, BRBN blue rubber bleb nevus syndrome, CCLA central conducting lymphatic anomaly, CLOVES congenital lipomatous overgrowth, vascular malformation, epidermal nevi, scoliosis/skeletal and spinal syndrome, CM capillary malformation, CMAVM capillary malformation-arteriovenous malformation, DCMO diffuse capillary malformation with overgrowth, EPHB4 ephrin B4, ERK extracellular signal-regulated kinase, Gαq guanine nucleotide-binding protein subunit alpha q, GDP guanosine diphosphate, GLA generalized lymphatic anomaly, GNA14 G protein subunit alpha 14, GRB2 growth factor receptor-bound protein 2, GTP guanosine triphosphate, KHE kaposiform hemangioendothelioma, KLA kaposiform lymphangiomatosis, KTS Klippel-Trenaunay syndrome, LM lymphatic malformation, MCAP megalencephaly-capillary malformation, MCM macrocephaly-capillary malformation, MVM multifocal (sporadic) venous malformation, NICH non-involuting congenital hemangioma, PHTS PTEN hamartoma tumor syndrome, PI3K/AKT/mTOR pathway phosphatidylinositol 3 kinase/protein kinase B/mammalian target of rapamycin pathway, PIP2 phosphatidylinositol 4,5-bisphosphate, PIP3 phosphatidylinositol 3,4,5-trisphosphate, PROS PIK3CA-related overgrowth syndrome, PTEN phosphatase and tensin homolog, RAS/MAPK/ERK Ras/mitogen activated protein kinase/extracellular signal-regulated kinase, RICH rapidly involuting congenital hemangioma, SOS son of sevenless homolog, SWS Sturge-Weber syndrome, TA tufted angioma, VEGF vascular endothelial growth factor, VEGFR2 vascular endothelial growth factor receptor 2, VM venous malformation, VMCM cutaneomucosal venous malformation

The PI3K/AKT/mTOR pathway is implicated in many cellular processes, such as cell-cycle regulation, proliferation, protein synthesis, and cell survival. It is also called the "anti-apoptosis pathway". It is the canonical signaling pathway used by TIE2 and is thus involved in the development of VMs.

TIE2 (encoded by the TEK gene) is a tyrosine kinase receptor that is specifically expressed on endothelial cells. Upon binding of angiopoietin-1, recruitment and activation of PI3K, phosphorylation and activation of AKT, and mTORC1 and 2 are set in motion, resulting in endothelial cell proliferation.[15]

Disturbances in the PI3K/AKT/mTOR pathway are associated with VMs, the majority (60%) being caused by gain-of-function somatic mutations in the TEK gene or (20%) the PIK3CA gene encoding the p110a catalytic subunit of PI3K.[12,13,16–19] All four subtypes of VMs (cutaneomucosal VM, VM, multifocal VM, and blue rubber bleb nevus [BRBN] syndrome) are associated with TIE2 mutations. The L914F mutation is the most frequently occurring, representing 60% of TIE2 mutations in sporadic VMs.

These mutations in either TIE2 or PIK3CA induce an excessive and unregulated activation of AKT. TIE2 mutations additionally cause phosphorylation of ERK1/2 and STAT.[19,20] The most frequently observed amino acid substitutions in PIK3CA (E542K, E545K, H1047R) are also encountered in cancer and other PIK3CA-associated malformations, such as LMs and overgrowth syndromes, including Klippel-Trenaunay syndrome (KTS), congenital lipomatous overgrowth, vascular malformation, epidermal nevi, scoliosis/skeletal and spinal syndrome (CLOVES), and megalencephaly-capillary malformation.[19,21,22] Somatic activating PIK3CA mutations were also identified in patients with GLA.[8]

The PI3K/AKT/mTOR pathway is inhibited by phosphatase and tensin homolog (PTEN). Loss of PTEN is another cause of abnormal stimulation of the PI3K/AKT/mTOR pathway. Germline loss-of-function mutations of PTEN cause PTEN hamartoma tumor syndrome, which includes vascular malformations as one of the minor clinical criteria.[23]

The second pathway that is often implicated in the development of vascular anomalies is the RAS/MAPK/ERK signaling pathway, mostly in fast-flow vascular malformations. It is often called the "proliferation pathway" because of its role in many cellular processes such as cell-cycle regulation, cell proliferation, and migration. Upstream elements include the guanine nucleotide-binding protein subunit alpha q (Gαq) encoded by GNAQ, GNA11, and GNA14. These Gα-subunit proteins exchange GDP for GTP when their receptor is activated, ultimately leading to the downstream activation of the RAS-MAPK (Raf/MEK/ERK pathway) and the PI3K/Akt/mTOR pathway (Figure 1).

Mutations in these genes are involved in congenital hemangiomas, including rapidly involuting congenital hemangiomas (RICH) and non-involuting congenital hemangiomas (NICH), in kaposiform hemangioendotheliomas (KHEs), congenital tufted angiomas, and pyogenic granulomas.[24,25] Somatic activating GNAQ mutations are implicated in isolated capillary malformations and Sturge-Weber syndrome.[26] Fast-flow AVMs are also driven by mutations in the RAS/MAPK/ERK pathway. RASopathies are diseases caused by genes in the RAS/MAPK/ERK pathway resulting in uncontrolled activation, such as neurofibromatosis. Several isolated vascular malformations should thus be considered as RASopathies, including capillary malformation-AVM 1 and 2, intra- and extracranial AVMs, and pyogenic granulomas.[27–29] An overview of these entities is detailed elsewhere.[30]