Defining and Targeting the Blood-Brain Barrier in Pediatric Glioma Subgroups
Abstract
Scientific Objective and Rationale: Brain tumors are now the leading cause of cancer-related death in children. Blood vessels in the brain form a specialized structure, termed the blood-brain barrier (BBB), which blocks most drugs from penetrating into the brain. The ability of drugs (traditional chemotherapies or newer small molecules) to reach tumor cells in the brain is a fundamental question in the field, and especially important for aggressive brain tumors like diffuse intrinsic pontine glioma (DIPG). Located in the brainstem, surgical resection is not an option, and no drugs have demonstrated significant survival improvements thus far. With an average survival of 6-9 months after diagnosis, and a 5-year survival rate of less than 1%, there is an urgent need to identify and develop new treatment methods. The objective of this proposal is to determine the mechanisms regulating BBB function across pediatric glioma subgroups and to test if suppressing DIPG Wnt signaling will alter BBB status to increase drug penetration and efficacy. The proposed study may identify new signals that regulate subgroup specific BBB properties and methods to increase drug penetration into difficult to treat brain tumors. Recent studies have shown widespread genetic heterogeneity in pediatric brain tumors, driving differences in tumor behavior and treatment response. One of these differences is tumor cell interaction with blood vessels and how they instruct vascular growth and BBB function. Previous work from the Principal Investigator (PI) demonstrated this in medulloblastoma subgroups and identified Wnt signaling as a regulator of brain tumor BBB function. Based on preliminary data from new pediatric glioma mouse models generated in the PI’s lab, we plan to expand upon this by identifying mechanisms that modulate BBB function and examine if suppressing Wnt signals generated by DIPG tumor cells improves BBB permeability, drug penetration, and treatment response. Career Goals: As an Assistant Professor in a joint position between the University of Cincinnati and Cincinnati Children’s Hospital Medical Center, the PI is committed to advancing the translation of brain tumor therapies by improving our understanding of BBB regulation and function. With a robust mentorship team, he is building a comprehensive research program focused on tumor-blood vessel interactions, developing novel tools to advance our understanding of new genetic and epigenetic causes of brain cancer, and exploring innovated methods to manipulate BBB function in brain tumors. In addition to regular interactions with his mentors, training in leadership and management, team and translational science, genomics, and pharmacology will be completed to help advance both proposed and future studies. Ultimate Application of Research: We will determine BBB functional differences in glioma subgroups using both our new pediatric glioma mouse models, and importantly, patient derived xenograft (PDX) samples from our collaborator Dr. Ester Hulleman at VUMC in the Netherlands (Aim 1). This will ensure data generated in mouse models accurately represents the human disease, maximizing translational potential. Suppression of DIPG Wnt signaling will be accomplished by genetic methods (Aim 2). A number of Wnt inhibitors are being tested in adult clinical trials, thus assessing pharmacological suppression of Wnt signaling could be quickly examined in our DIPG mouse model. With no current therapeutic options for DIPG patients, promising data from our mouse models may be moved forward into Phase 1 trials within 5+ years. Improving drug penetration into brain tumors would be a major breakthrough to improve treatment response and patient outcome. Genomics has identified unique drug targets within tumor subgroups, but determining subgroup differences in the ability of drugs to reach brain tumors will be essential as we proceed into an exciting era of precision medicine. Defin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810291
Entities
People
- Timothy N. Phoenix
Organizations
- United States Army
- University of Cincinnati