mTORC1 Inhibitor Rapamycin Inhibits Growth of Cerebral Cavernous Malformation in Adult Mice.

Abstract

Cerebral cavernous malformations (CCMs) are vascular malformations that frequently cause stroke. CCMs arise due to loss of function in one of the genes that encode the CCM complex, a negative regulator of MEKK3-KLF2/4 signaling in vascular endothelial cells. Gain-of-function mutations in <i>PIK3CA</i> (encoding the enzymatic subunit of the PI3K (phosphoinositide 3-kinase) pathway associated with cell growth) synergize with CCM gene loss-of-function to generate rapidly growing lesions. We recently developed a model of CCM formation that closely reproduces key events in human CCM formation through inducible CCM loss-of-function and <i>PIK3CA</i> gain-of-function in mature mice. In the present study, we use this model to test the ability of rapamycin, a clinically approved inhibitor of the PI3K effector mTORC1, to treat rapidly growing CCMs. We show that both intraperitoneal and oral administration of rapamycin arrests CCM growth, reduces perilesional iron deposition, and improves vascular perfusion within CCMs. Our findings further establish this adult CCM model as a valuable preclinical model and support clinical testing of rapamycin to treat rapidly growing human CCMs.