Project 1: Venous Malformation

Venous Malformations (VM) is a developmental chronic vascular anomaly characterized by massively dilated (ectatic) veins with hyperactive somatic mutations of the TIE2 kinase receptor. Through the generation of a revolutionary patient mutation-based xenograft model of VM we assessed the efficacy of the mTOR inhibitor rapamycin in preventing expansion of the lesions in mouse. The success of our discovery culminated into efficacious and safe targeted treatment with Sirolimus (rapamycin) in patients affected by VM.

We further performed an unbiased drug screening and determined that Abelson protein kinase 1 (c-ABL) inhibitors reduced TIE2 mutant-endothelial cell (EC) proliferation. When combined with rapamycin, the c-ABL inhibitor Ponatinib promoted significant VM lesion regression. The efficacy of ABL kinase inhibitors on TIE2-mutated EC prompted us to discover that TIE2 signaling promotes c-ABL activation, while c-ABL targeting significantly reduced vascular channel size.

We are currently investigating the cellular and molecular determinants of TIE2 driven lumen expansion with the use of our xenograft model and a 3D system modeling the VM vascular defects.

(See figures 1.1-1.4)

Project 2: Capillary Lymphatic Venous Malformation

Capillary lymphatic venous malformations (CLVM) are complex vascular anomalies that appear during fetal development and cause life-long complications such as coagulopathy, pulmonary embolism, chronic pain, and severe disfigurement. Non-inherited, (somatic) mosaic mutations in the 110-kD catalytic α-subunit of phosphoinositide-3-kinase (PIK3CA) gene have been identified in affected tissues from CLVM patients.

In collaboration with the laboratory of Dr. Timothy Le Cras we are currently testing the hypothesis that PIK3CA mutations originate in the EC population of CLVM lesions. To test our hypothesis, we devised a protocol to isolate and purify EC from human CLVM lesion tissue. To study the EC contribution to disease, we are generating a xenograft model by injecting patient-derived EC into mice. Our future studies will focus on the identification of novel molecular targeted therapies, biomarkers and crosstalk between EC and stromal cells.

(See figures 2.1-2.2)