Vascular malformations: An overview of their molecular pathways, detection of mutational profiles and subsequent targets for drug therapy

Ann Mansur, Ivan Radovanovic, Ann Mansur, Ivan Radovanovic

Abstract

Vascular malformations are anomalies in vascular development that portend a significant risk of hemorrhage, morbidity and mortality. Conventional treatments with surgery, radiosurgery and/or endovascular approaches are often insufficient for cure, thereby presenting an ongoing challenge for physicians and their patients. In the last two decades, we have learned that each type of vascular malformation harbors inherited germline and somatic mutations in two well-known cellular pathways that are also implicated in cancer biology: the PI3K/AKT/mTOR and RAS/RAF/MEK pathways. This knowledge has led to recent efforts in: (1) identifying reliable mechanisms to detect a patient's mutational burden in a minimally-invasive manner, and then (2) understand how cancer drugs that target these mutations can be repurposed for vascular malformation care. The idea of precision medicine for vascular pathologies is growing in potential and will be critical in expanding the clinician's therapeutic armamentarium.

Keywords: liquid biopsy; precision medicine; signaling pathway; targeted therapy; vascular malformation (VMs).

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2023 Mansur and Radovanovic.

Figures

Figure 1
Figure 1
Two major cellular signaling pathways implicated in the development of vascular malformations. TIE2 RTK, TEK gene receptor tyrosine kinase; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor.
Figure 2
Figure 2
Mutations and targeted therapies for slow-flow malformations. TIE2 RTK, TEK gene receptor tyrosine kinase; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor. Somatic TIE2 mutations are observed in unifocal and multifocal venous malformations (VeMs), blue rubber bled nevus syndrome (BRBN) and cutaneomucosal venous malformations. Somatic PIK3CA mutations are seen in venous malformations, lymphatic malformations and PROS. Some central lymphatic anomalies such as Gorham Stout Disease (GSD) and kaposiform lymphangiomatosis (KLA) harbor RAS mutations while patients with central conducting lymphatic anomalies (CCLA) have ARAF mutations. Currently investigated targeted therapies for each component of the pathway in slow-flow malformations are shown in red.
Figure 3
Figure 3
Mutations and targeted therapies for slow-flow malformations. HHT1 is known to have multiple affected loci in the BMP signaling pathway that generally act to inhibit the PIK3CA pathway in the wild-type state. CM-AVM 1 is characterized by a LOF mutation in RASA1, while CM-AVM2 has the mutation in the EphB4; both activate the KRAS pathway in the wild-type state. Targeted therapies for HHT include bevacizumab, pazopanib and thalidomide. There is a potential to also explore PI3KCA with Alpelsib for HHT. Targeted therapies for CM-AVM include Trametinib, while those for sporadic AVMs include bevacizumab, thalidomide, and Trametinib.

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