Project Funding Details

Since most drugs do not efficiently cross the BBB, it presents a fundamental challenge to treating DIPGs. However, the mechanisms that regulate BBB function in DIPG remain poorly understood. In the normal brain, the BBB is established and maintained by Wnt ligands secreted from the surrounding CNS microenvironment. Prior studies by our group and others have shown that brain tumors can secrete factors that promote angiogenesis (i.e. - VEGFA) and BBB permeability (i.e. - WIF1/DKK1). Yet, if brain tumors secrete factors that actively promote BBB integrity has not been investigated. Identifying mechanisms that regulate DIPG BBB function, and their relationship to normal BBB maintenance, will be critical to advance our understanding of DIPG biology and to improve the therapeutic efficacy of systematically delivered drugs. Angpt1 is a secreted ligand that activates the endothelial Tie2 receptor. Previous studies have shown Angpt1-Tie2 signaling promotes endothelial survival and can reduce VEGF induced vascular permeability in different organs. Angpt1 is not expressed at appreciable levels in the healthy brain (GTex, Allen Brain Atlas, Human Protein Atlas databases), but is up regulated in select brain tumors, including H3F3A K27M mutant DIPG. Inhibition of Angpt1-Tie2 signaling in our DIPG model by overexpression of the Tie2 antagonist Angpt2 causes increased BBB permeability. These findings form the basis of our hypothesis that Angpt1Tie2 signaling plays a central role in promoting DIPG BBB integrity. The central objectives of this proposal will be to characterize the expression, function, and mechanisms by which Angpt1 promotes BBB integrity in DIPG. The long-term goal is that our results will provide a novel method to specifically manipulate the DIPG BBB to improve drug penetration and patient outcome.

In order to enter brain tissue, molecules and cells in the circulation coursing through the central nervous system (CNS) must first cross a specialized biological border in blood vessel walls called the blood-brain barrier (BBB). Drug penetration across the BBB presents a fundamental challenge to effective treatment of many brain tumors, including diffuse intrinsic pontine gliomas (DIPGs), which are unresectable and only temporarily respond to radiation treatment. Dr. Phoenix will characterize the mechanisms that regulate Angiopoietin-1 (Angpt1) expression and function in DIPG and determine the potential of Angpt1-Tie2 inhibition to effect tumor-specific increases in BBB permeability and drug penetration. Findings will open the door for new approaches to manipulating the BBB in DIPG and ultimately better clinical outcomes for the children diagnosed.