Lymphatic malformations: mechanistic insights and evolving therapeutic frontiers

Targeting lymphatic function in cardiovascular-kidney-metabolic syndrome: preclinical methods to analyze lymphatic function and therapeutic opportunities

“…Many of the preclinical techniques that probe lymphatic function have shown translatability into the clinic and therapeutic advancement. Most of the successes have been made in the field of lymphatic anomalies, which is not unsurprising as this collection of diseases are primarily the direct result of lymphatic dysfunction ( 60 , 108 ). Lymphatic anomaly is an umbrella term that includes diseases of lymphatic inactivation, such as primary lymphedema, and lymphatic overactivation, such as malformations ( 59 ).…”

“…Lymphatic malformations are sporadic, making diagnosis and management difficult ( 60 ). However, several somatic drivers of the lymphatic malformations have been identified as causative genes, which has greatly advanced understanding of the disease and has led to clinical optimism ( 108 ). For example, next generation sequencing has identified somatic gain-of-function mutations in PIK3CA , which encodes phosphatidylinositol-4,5,-bisphosphate 3-kinase (PI3K), as causal for cystic lymphatic malformations and a variety of phenotypically distinct complex lymphatic anomalies ( 116 , 117 ).…”

“…Other ongoing clinical efforts follow a similar paradigm and focus on using FDA-approved a cancer therapies, such as sirolimus and damentib/trametinib drugs to inhibit mTOR and MEK, respectively ( 108 ). As mentioned in previous sections, evidence suggests that lymphatic contribution to CKM syndrome may be due to lymphatic vascular insufficiency and rarefaction ( 23 , 24 ).…”

“…Therefore, fine-tuning is an important consideration for therapeutic exploration. However, ongoing clinical trials show a clear proof-of-concept that genetic testing and translatable imaging techniques can identify lymphatic drivers of disease and test the efficacy of targeted therapeutics ( 60 , 108 ). Application of this strategy may allow quick progression of lymphatic-specific therapies in CKM syndrome.…”