Pathogenesis and Treatment of Kaposiform Lymphangiomatosis

Kaposiform lymphangiomatosis (KLA) is a devastating congenital lymphatic anomaly with a 51% survival at 5 years, and 34% overall. KLA patients suffer from pleural and cardiac effusions and coagulopathy leading to the high morbidity and mortality. The histopathology of KLA features lesions containing clusters of spindle- shaped endothelial cells accompanying malformed lymphatic vessels typically in the lungs, spleen, abdomen, and/or liver. The role, origin and function of these characteristic spindled endothelial cells is unclear. Definitive diagnosis of KLA is often delayed due to the complex symptoms and the risks of biopsy due to the coagulopathy. As part of a clinical trial using sirolimus (rapamycin; mTOR inhibitor) we were the first to identify a blood biomarker for KLA, angiopoietin-2 (ANG-2), that may provide important insights into the underlying disease mechanisms. ANG-2, which can act as a pro-angiogenic factor, was highly elevated in KLA patients and decreased with sirolimus treatment suggesting that dysregulation of ANG-2 in KLA is dependent on mTOR signaling. Additional possible insights into pathogenesis of KLA have come from the identification of a somatic mutation NRAS Q61R in lesion tissue from patients. Q61R is an NRAS activating mutation in >20% of melanomas and other cancers; however, its role in human endothelial cells and vascular malformations is unclear. Our preliminary studies with human endothelial cells suggest that NRAS Q61R is upstream of ANG- 2 and induces the spindled endothelial cell morphology in KLA lesions. Proposed studies will identify the processes and pathways involved in this regulation and help move the understanding of KLA pathogenesis forward. The goal of this proposal is to test the hypothesis that NRAS Q61R mediates the pathogenesis of KLA by increasing MAPK and PI3K-AKT-mTOR signaling, inducing spindled endothelial cells, upregulating ANG-2 expression, and so driving abnormal lymphangiogenesis. We have developed unique in vitro and in vivo models to test this hypothesis and preliminary data from our laboratory strongly supports this proposed mechanism and demonstrates the feasibility of our approach. These studies will address a critical knowledge gap in KLA. We will test new therapeutic targets since the current treatment, sirolimus, at best only induces a partial clinical response. Our long-term goals are to elucidate the cellular and molecular pathogenesis of KLA and identify new therapeutic targets. We are uniquely positioned having the expertise and experimental models in hand.