CCM lesions develop when blood vessel cells (endothelial cells) lose the function for one of the CCM genes. New research shows us that, for those lesions that are actively growing and causing symptoms, the endothelial cells also have acquired mutations in a common cancer-causing gene called PIK3CA. This discovery adds to the body of knowledge related to CCM biology and identifies a new target for treatment and a possible class of medicine.
What is PIK3CA?
PIK3CA is a gene commonly mutated in cancers. Gain-of-function mutations turn on the gene, sending it into overdrive to stimulate cell proliferation and growth.
Did I inherit a PIK3CA mutation?
The PIK3CA mutation found in aggressive CCM lesions is a somatic mutation. Somatic mutations develop by chance in cells of the body (not sperm or eggs). They are not inherited, nor can they be passed on to the next generation.
In the new study, PIK3CA and CCM mutations fuel cavernomas through a cancer-like mechanism, published in the prestigious journal, Nature, we learn that somatic mutations in genes other than the CCM genes play an essential role in CCM lesion growth. This is true in both sporadic and familial forms of CCM disease.
How did the researchers learn this?
The consortium research team from the University of Pennsylvania, Duke, and the University of Chicago carefully studied the genetics of individual endothelial cells from lesions. In both sporadic and familial cases, they discovered a proportion of the samples where some of the blood vessel cells had as many as three somatic mutations. The mutations included loss-of-function mutations in both copies of the CCM gene and a gain-of-function mutation in PIK3CA.
What does PIK3CA activation do?
The activation of PIK3CA is biologically relevant because it stimulates growth through a signaling network (a network of molecules that interact with each other). That network includes another molecule, called mTor. mTor is a key component of cell metabolism and growth. When the network is disturbed by PIK3CA activation, mTor becomes misregulated, too. The resulting change in signaling contributes to cancer, overgrowth syndromes, and metabolic and autoimmune disorders.
Is CCM a form of cancer?
mTor is overactive in CCM lesions and contributes to the rapid clonal expansion and cancer-like growth of these lesions. However, although the growth of an individual lesion is cancer-like, CCM lesions do not metastasize and spread the way malignant cancers do.
What does this tell us about possible treatment?
Interestingly, mTor is also overactive in other vascular and lymphatic malformations that already have treatments. Specifically, the FDA-approved drug rapamycin (sirolimus) targets mTor and blocks its activity.
Using mouse models, the study team showed that rapamycin treatment decreases lesion numbers in the acute neonatal model and inhibits lesion growth in mature CCMs. These findings suggest that rapamycin or another drug in its class may become a treatment for fast-growing lesions, those that are known to most commonly cause stroke, seizure and are associated with hemorrhage.
According to Mark Kahn, MD, senior author of this study,
By discovering that most aggressive, surgical CCMs harbor gain of function PIK3CA mutations and that we can prevent CCM growth by blocking that pathway, we think we have identified a mechanism that is truly druggable. Rapamycin and similar drugs that block mTORC1 are already FDA approved and this pathway is already a big target for cancer drugs that can be potentially also applied to CCM disease. In comparison with some of our other recent findings, e.g., the microbiome, I think this has more direct and more rapid translation to the clinic.
Are there other studies that relate to these findings?
New technologies and technique refinement are helping to accelerate the field of somatic cell genetic research, particularly at the single-cell level. In a related study, a Chinese research team found somatic mutations in CCM1, CCM3, PIK3CA, and in MAP3K3. MAP3K3 is a known player in CCM signaling, and the authors suggest the additional somatic mutation may contribute to the clinical variability between individuals affected by CCM. It remains to be seen how many other genes may harbor somatic mutations and contribute to CCM lesion development, growth, and/or activity.