Scientists have shown in new research how cerebral cavernous malformations (CCMs) can lead to seizures or stroke, plus how an existing cancer drug can be used to check this.
CCMs are clusters of blood vessels in the brain that become dilated and malformed over time. They are a type of benign tumor and are present in roughly 0.2% of the population.
In this study led by Mark L. Kahn, M.D., a professor at the University of Pennsylvania’s Perelman School of Medicine, researchers found that the cancer-causing gene PIK3CA could worsen existing blood vessel malformations in the brain, thus encouraging seizures or stroke.
Formation of CCMs
The growth of abnormal brain blood vessels normally results when proteins that typically inhibit uncontrolled vascular growth become dormant.
Inherited mutations are believed to be responsible for up to 50% of cases of these malformed blood vessels in the brain.
Researchers observed in earlier studies that environmental factors also play a role in the formation of CCMs. Among these factors are changes in the gut microbiome.
Research also reveals a link to inactivating mutations in a group of genes described as the “CCM complex.”
Those previous studies helped to understand the initial formation of malformed blood vessels. However, they did not explain why these malformations suddenly experience a rapid growth in size to cause seizures or stroke.
In the new research, Kahn and his team set out to find an explanation for the phenomenon.
Cancer-causing gene mutations and CCMs
The research team found that mutations in the cancer-causing gene PIK3CA were to blame for the sudden growth of CCMs. This was after using mouse models of CCM formation and looking at tissue samples from human CCMs.
New mutations in the oncogene that is known to promote breast and cervical cancers cause existing CCMs to grow rapidly.
Evaluation of human CCM tissue samples revealed that about 71 percent had mutations in PIK3CA. Investigations revealed a “cancer-like” mechanism that causes malformed blood vessels in the brain to grow suddenly.
The researchers think cases of accelerated growth of malformed brain blood vessels involve a multistep genetic process. The first of the steps is the malfunction of CCM suppressor genes. This is followed by the activation of the PIK3CA gene expression.
PIK3CA mutations seen in cases of cancer and said to worsen CCMs cause an increase in PI3K-mTOR signaling. The drug rapamycin (sirolimus) helps to control the signaling pathway, which is why it is used for treating tumors.
Kahn and his colleagues were able to reduce CCM formation considerably in genetic mouse models with the aid of rapamycin. This indicates that the drug could be beneficial for treating brain blood vessel malformations.
The researchers continue to investigate CCM causes and whether their findings can help for the treatment of people with aggressive cases. Aggressive CCM lesions can at present only be treated with surgery.