An acquired mutation in the cancer-causing gene PIK3CA can make blood vessel malformations in the brain worse, possibly explaining why these abnormal clusters sometimes rapidly increase in size and cause stroke or seizures, shows new research.
Cerebral cavernous malformations (CCMs) are a type of hemangioma, present in around 0.2% of the population, and are essentially a form of benign, vascular tumor. Clusters of blood vessels in the brain become dilated and malformed, changing in size and structure over time.
The reason these growths form in the brain is thought to be partly inherited mutations, accounting for 30-50% of cases, and partly environmental. They occur when proteins that normally stop excess vascular growth become inactive. While they can lie dormant in the brain for a long time, they sometimes undergo sudden, rapid growth that can cause strokes and seizures.
Mark Kahn, M.D., a professor at the Perelman School of Medicine, University of Pennsylvania, and Douglas Marchuk, Ph.D., a professor at Duke University School of Medicine, led a research project to investigate causes of sudden growth and worsening of these non-cancerous tumors.
Looking both at tissue samples from human CCMs and a mouse model of these vascular malformations the researchers discovered that new mutations in an oncogene called PIK3CA, thought to promote growth of some cervical and breast cancers, are behind the sudden growth seen in some CCM cases.
They believe there is a multistep genetic process in these cases: the first step of which involves failure of the CCM suppressor genes; and then the second step activation of the PIK3CA expression, which promotes fast growth in a similar fashion to a malignant tumor.
In samples taken from 79 human CCM’s that required surgical intervention the team evaluated the genotype for 66 genes thought to be involved in their formation. Approximately 71% of the samples had mutations in the PIK3CA gene.
“The most significant conceptual advance of this study is the discovery of a compound genetic mechanism of vascular malformation pathogenesis,” write the authors in the journal Nature.
“By analogy to cancer, the CCM genes may be considered vascular ‘suppressor genes’, required to constrain vessel growth, while PIK3CA may be considered a vascular ‘oncogene’, capable of driving excess vascular growth. As in cancer, the combined loss of a vascular suppressor and gain of a vascular activator is a potent combination that culminates in aggressive, symptomatic disease.”
Rapamycin (sirolimus) is a natural antibiotic and antifungal and is also an immune suppressant. Mutations in the PIK3CA gene seen in cancer increase PI3K-mTOR signaling, something rapamycin is known to inhibit.
The researchers tested rapamycin as a possible treatment for CCM’s that undergo rapid growth in a mouse model and found it effectively reduced CCM formation in the animals. They are now assessing whether this finding can be used to help treat people with aggressive CCM’s, which can currently only be treated with surgery.
“Although aggressive CCM lesions are relatively rare, they account for virtually all of the strokes and neurologic symptoms associated with this disease and they can presently only be treated by surgical resection,” write the researchers.
“Sirolimus [rapamycin] has recently been used successfully to treat lymphatic and venous/slow flow vascular malformations that are associated with identical PIK3CA gain of function mutations, and newer agents directly targeting PIK3CA itself have also been found to be effective for treatment of inoperable vascular malformations… It is reasonable to predict that such drugs will also be effective for treatment of aggressive CCM lesions.”
