Based on the published clinical dat

Based on the published clinical data thus far, it seems evident that sirolimus can significantly ameliorate symptoms and diminish lesion volumes in patients with complicated vascular anomalies. Although reports on long-term efficacy are still lacking, sirolimus is unlikely to be completely curative in most patients . One intriguing yet unexploredpossibility to boost treatment results could be the combination of sirolimus with MAPK inhibition. Sirolimus was not able to normalize all VM cellular phenotypes in vitro and in fact increased Erk1/2 phosphorylation, which could potentiate some of the cellular abnormalities . mTORC1 inhibition with sirolimus has been shown to induce negative feedback regulation leading to increased activation of PI3K, Akt, S6K1 and Erk pathways, likely limiting its efficacy in cancer and perhaps also in vascular anomalies . Clinically approved Mek inhibitors (trametinib, cobimetinib) exist, which could be considered for repurposing to vascular anomalies as a combination therapy with sirolimus if first shown beneficial in preclinical models