PI3K/mTOR inhibition promotes the regression of experimental vascular malformations driven by PIK3CA-activating...

Area of Science:

• Genetics and Molecular Biology
• Vascular Biology
• Medical Research

Background:

• Somatic activating mutations in the PIK3CA gene are linked to vascular malformations (VM), including those associated with overgrowth syndromes like CLOVES and Klippel-Trenaunay syndrome.
• Extended or recurrent VM necessitate novel therapeutic strategies beyond current treatments.

Purpose of the Study:

• To investigate the role of PIK3CA mutations in VM pathogenesis.
• To evaluate the efficacy of PI3K/mTOR inhibitors in treating PIK3CA-driven VM using a mouse model.

Main Methods:

• Generation of a mouse model for VM through local endothelial cell expression of PIK3CA-activating mutations.
• Administration of dual PI3K/mTOR inhibitor (BEZ235) and mTOR inhibitor (Everolimus) to assess therapeutic effects.
• Analysis of human endothelial cells with PIK3CA mutations to study proliferation, senescence, and angiogenic sprouting.

Main Results:

• PIK3CA-driven lesions in mice exhibited hemorrhage, hyperplastic vessels, inflammation, and increased endothelial cell density.
• PI3K/mTOR inhibitors (BEZ235, Everolimus) ameliorated these vascular lesions in the mouse model.
• In human endothelial cells, PIK3CA mutations increased proliferation and senescence, and promoted angiogenic sprouting; PI3K/mTOR inhibitors normalized proliferation and reduced senescence.

Conclusions:

• PIK3CA mutations play a critical role in the development of vascular malformations.
• PI3K/mTOR inhibitors demonstrate significant therapeutic potential for PIK3CA-driven vascular malformations, offering a promising treatment avenue.