Researchers have identified a substance that reduces blood vessel lesions in the brain in the disease Cerebral Cavernous Malformation (CCM). The substance is already used to treat brain tumours in children and could therefore relatively rapidly be repurposed to treat CCM, hopefully replacing surgery as the currently only treatment option.
In the disease Cerebral Cavernous Malformations (CCM), fragile, mulberry-like malformed blood vessel structures are formed in the brain. This can cause hemorrhages and, in some cases, acute bleedings (stroke). Currently, the only treatment option is surgery to remove the lesions. As patients often present with multiple lesions, there is an urgent need to develop non-invasive therapeutic strategies.
In the present study the researchers have identified a substance that was shown to reduce both the number and size of the vascular malformations.
"We tested more than 5,000 bioactive molecules on cultured CCM mouse vascular cells to identify compounds that could normalise their pathogenic phenotype. Top drug candidates were subsequently studied in cultured human brain vascular cells and in CCM animal models. The most promising results came from dabrafenib, a BRAF inhibitor that efficiently reversed the pathological phenotype in vitro and halted cavernoma progression in vivo. Remarkably, dabrafenib targeted two pathological signalling pathways that contribute to CCM development and progression, says Maximiliano Arce, first and co-corresponding author of the study.
To investigate whether dabrafenib could work as a drug to treat CCM, the researchers tested its effect in a mouse model with CCM. They found that in addition to reducing the number and size of the lesions, dabrafenib treatment stabilised the vessels and suppressed lesion leakage. It could also rescue abnormal structural defects in the vasculature of the eye retina, which can also in some cases occur in CCM patients.
An advantage with dabrafenib is that it is a substance which is already used as a drug, currently to treat low-grade glioma, a brain tumour type in children. The results from the new study support the repurposing of dabrafenib as a therapeutic drug for CCM.
"Since dabrafenib is already approved by the U.S. Food and Drug Administration and the European Medicines Agency, and has an established safety profile, it represents a strong candidate for rapid clinical translation to halt brain cavernoma growth and progression, says Peetra Magnusson, who led the study.
The study was performed in collaboration with researchers at SciLifeLab BioImage Informatics Unit.
