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Updated: Dec 18, 2025
A Patient-Derived Xenograft Model for Venous Malformation
Published on: June 15, 2020
New and Emerging Targeted Therapies for Vascular Malformations
An Van Damme1,2, Emmanuel Seront1,3, Valérie Dekeuleneer1
1Center for Vascular Anomalies, Division of Plastic Surgery, VASCERN VASCA European Reference Centre, Saint Luc University Hospital, Avenue Hippocrate 10, 1200, Brussels, Belgium.
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.
Insights
Vascular malformations, caused by genetic mutations, are increasingly treated with targeted cancer drugs. Sirolimus and alpelisib show promise in managing these complex vascular disorders.
Area of Science:
- Vascular biology and genetics
- Molecular mechanisms of disease
- Oncology drug repurposing
Background:
- Vascular malformations are congenital disorders of blood and lymphatic vessel development.
- Historically managed with surgery and sclerotherapy, their genetic underpinnings are now understood.
- Mutations in RAS/MAPK/ERK and PIK3/AKT/mTOR pathways are implicated in their pathogenesis.
Purpose of the Study:
- To review the current understanding of genetic mutations in vascular malformations.
- To explore the therapeutic potential of targeted molecular inhibitors.
- To highlight the repurposing of cancer drugs for vascular malformation treatment.
Main Methods:
- Review of genetic studies identifying mutations in vascular anomalies.
- Analysis of clinical data on targeted therapies, particularly mTOR inhibitors like sirolimus.
- Investigation into emerging treatments such as PIK3CA inhibitors (e.g., alpelisib).
Main Results:
- Vascular malformations are linked to hyperactivation of RAS/MAPK/ERK and/or PIK3/AKT/mTOR pathways.
- Sirolimus demonstrates efficacy in treating venous, lymphatic, and complex malformations.
- Emerging data supports targeted therapies like alpelisib for specific mutations.
Conclusions:
- Targeted molecular therapies, especially repurposed cancer drugs, represent a paradigm shift in managing vascular malformations.
- Understanding the genetic basis allows for personalized treatment strategies.
- Further research into these pathways and inhibitors is crucial for optimizing patient outcomes.
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