Also, we review the latest advances in phosphoinositide 3-kinase (PI3K) inhibitors in the clinic and their repurposing for the treatment of lymphatic malformations and venous malformations.
Culprit gene mutations typically involve two major signaling pathways; the RAS/MAPK/ERK pathway is typically involved in fast-flow arteriovenous malformations, whereas the PI3K/AKT/mTOR pathway is typically mutated in slow-flow venous and lymphatic malformations.
Recognizing that different mutations activate PI3K to varying degrees, we developed a metric, the genotype-adjusted VAF (GVAF), to account for differences in mutation strength, and found significantly higher GVAFs in LMs with more severe clinical characteristics including orofacial location or microcystic structure.
The activation of a central growth/survival pathway (PI3K/AKT) represents a feasible target for the non-invasive treatment of LMs bearing in mind that background genetics may individualize lesions and influence treatments.