Researchers have discovered an explanation why cerebral cavernous malformations (CCMs) – clumps of dilated blood vessels in the brain – can suddenly develop and cause seizures or a stroke. Specifically, they found that a specific acquired mutation in a carcinogenic gene (PIK3CA) could exacerbate existing CCMs in the brain. In addition, the reuse of an already existing anticancer drug has shown promise in mouse models of CCM to improve brain-vascular health and prevent bleeding in brain tissue.
Previous studies have linked the initial formation of CCMs to various environmental factors, including differences in the gut microbiome and inactivating mutations in three specific genes collectively known as the “CCM complex”. While these changes were enough to cause small deformities to form in the brain, they did not explain why some suddenly grew in size, leading to seizures or a stroke.
Using mouse genetic models of CCM formation, the researchers found that it is the extra ‘hit’ that stimulates the known carcinogenic PIK3CA gene and leads to the rapid growth of existing CCMs. When they examined the resected human CCM tissue, they saw that the same genes were involved, supporting the idea of a “cancer-like” mechanism for accelerated growth of blood vessel malformations in which small CCMs quiescent cells become “malignant” after a new genetic mutation occurs.
In cancer, the PIK3CA mutation results in an increase in PI3K-mTOR signaling, which is a well-established drug target for the treatment of tumors. Rapamycin is an FDA-approved drug that inhibits this same signaling pathway and has been used to treat malformations of the veins and lymphatic system. Here, rapamycin dramatically reduced TLC formation in genetic mouse models, suggesting that it could potentially be used as a treatment.
The study was led by Mark L. Kahn, MD at the Perelman School of Medicine, University of Pennsylvania, Philadelphia. His team continues to study the causes of CCM formation and growth, and suggests that further analysis of human CCM lesions and clinical testing of rapamycin and similar drugs is needed to determine if this mechanism may be a target. for therapy.
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Material provided by NIH / National Institute of Neurological Disorders and Stroke. Note: Content can be changed for style and length.