Pathogenesis and Treatment of Capillary Venous Lymphatic Malformations
Principle Investigator: Timothy LeCras, PhD
Capillary Lymphatic Venous Malformations (CLVM) are malformations characterized by abnormal overgrowth of capillaries, lymphatic vessels, veins, and soft tissue. CLVM that is present at birth, never regresses and expands with time. CLVM is a mostly syndromic disease that is debilitating, difficult to treat, and results in a lifetime of disfiguration and dysfunction. Partial foot amputation often is required in children to maintain the ability to walk. CLVM lesions located on vital structures can lead to death. Surgery and interventional procedures are the current mainstay of treatment, but patients often require multiple procedures as lesions often regrow. A major problem in developing new therapies is that the underlying mechanism(s) driving the formation of CLVM is unclear, so medical treatments are lacking.
Our research addresses this problem using patient-derived cells, as well as a novel mouse model to study the disease process. Mutations in the phosphatidylinositol-4,5-bisphospate 3-kinase catalytic subunit alpha (PIK3CA) gene have been identified in CLVM tissue. We have preliminary data that show that, in the majority of patients, the cell type that exclusively expresses the PI3KCA mutations is in the endothelial cells that line the blood vessels (EC) in CLVM. We are working to generate a novel murine model by implanting CLVM-EC. We will use this model to test the efficacy of drugs targeting the abnormal PIK3CA pathway. These genetic studies will help to define the signaling pathways that drive the disease process. This knowledge could be used to test new drug targets. Identification of new therapeutic targets that provide effective medical treatment would dramatically improve the lives of CLVM patients.