CLOVES syndrome is a rare condition that is characterised by tissue overgrowth and vascular abnormalities, caused by mosaic gain-of-function mutations in the PIK3CA gene. The way in which CLOVES syndrome manifests itself is highly variable but common features include fatty overgrowths, vascular anomalies, kidney problems and spinal-related symptoms. The condition has no specific treatment and a low survival rate. It is one of a number of conditions that can be grouped under the umbrella of PIK3CA-related overgrowth syndromes (PROS).
By initially undertaking research on a mouse model, and subsequently with human patients, it has been shown by Dr Guillaume Canaud and his team at the Necker-Enfants Malades Hospital in Paris, that BYL719 (an inhibitor of PIK3CA, currently undergoing clinical trials for treating PIK3CA dependent tumours) can prevent and improve organ dysfunction and can improve disease symptoms in patients suffering from CLOVES syndrome.
A mouse model of CLOVES syndrome
The researchers generated mice that express a PIK3CA transgene upon the administration of tamoxifen, mimicking the activity of human CLOVES syndrome. These mice showed similar symptoms to human sufferers of CLOVES, with MRI revealing scoliosis, kidney cysts and muscle abnormalities. Subsequent histological examination revealed further organ abnormalities including additional kidney problems, and abnormalities in the liver and spleen. Furthermore, a high level of cell proliferation was observed in all of the affected organs.
Rapamycin or BYL719?
Rapamycin has previously shown evidence of improving vascular malformations, and when tested on the mouse model of CLOVES syndrome it improved survival rate. However, it did not improve organ abnormalities and did not significantly reduce tumour growth. In contrast, mice treated with BYL719 were found to have preserved tissues and normal vessels. Importantly, BYL719 administration strongly reduced cell proliferation in all affected organs. Withdrawal of BYL719 led to the recurrence of tumours within four weeks, suggesting that continuous administration of BYL719 could relieve the symptoms of CLOVES syndrome.
BYL719 leads to huge improvements in patients with CLOVES syndrome
BYL719 was initially administered to two patients suffering with CLOVES syndrome, who both, after being treated with BYL719, showed dramatic and rapid improvement in their condition. There was a major reduction of vascular tumour abnormalities and overgrowths in addition to improved renal function and a significantly increased quality of life in both patients. The only observed side-effect was hyperglycaemia, which was able to be controlled by a controlled diet.
On the basis of these initial results, Canaud and his team were given permission to treat 17 additional patients with CLOVES syndrome by administering BYL719. The 14 children and 3 adults all showed substantial clinical improvement. A reduction in size of vascular tumours was observed in all of the patients, as well as a drastic reduction in metabolic activity of affected areas. In addition to an improvement to skin capillary abnormalities and scoliosis, all patients reported decreased tiredness. The growth of the children was not affected during the 6 months of treatment and the only side-effects seen were discrete mouth ulcerations in 3 patients (that ultimately disappeared spontaneously) and the aforementioned hyperglycaemia.
The IMPC is aiming to design and produce a genome-wide mouse strain resource of human disease-associated coding variants associated with rare disease that can be used for validation of putative functional variants and insight into disease mechanism(s). To find out more, click here.
Research paper: Targeted therapy in patients with PIK3CA-related overgrowth syndrome