Description
- Abstract:
- Abstract of Breaking Barriers: Evaluating GSK-3 Inhibition as a Dual Therapeutic Strategy in Diffuse Midline Glioma Models, by Jasmine Sharee Clark, Ph.D., Brown University, May 2026 Diffuse midline glioma (DMG) is a highly invasive and fatal pediatric brain tumor that arises from glial cells within the pons of the brainstem. Despite focal radiation treatment, DMG continues to have a poor prognosis, with a median survival of less than 10 months. A significant challenge in treating DMG is the blood-brain barrier (BBB), which tightly restricts access to therapeutic agents, preventing effective drugs from reaching the brain at effective concentrations. Glycogen synthase kinase-3 (GSK-3) has emerged as a promising therapeutic target due to its critical roles in regulating cell migration, angiogenesis, and endothelial barrier function. This thesis investigated the effects of GSK-3 inhibition on pediatric glioma models using the multi-kinase indirubin derivative 6-bromoindirubin-3′-acetoxime (BIA) and the selective GSK-3 inhibitor CHIR99021 (C91) in various assays. We observed that both BIA and C91 dramatically suppressed proliferation while significantly reducing collective and individual migration of pediatric glioma cells over time. In 3D BBB/BTB spheroid models, both compounds increased barrier permeability and antibody uptake, with BIA also showing robust dextran uptake. Our hypothesis is that GSK-3 inhibition could be an effective therapeutic approach for DMG by targeting tumor cell migration and improving drug delivery through modulation of barrier function. Unlike BIA’s broader kinase inhibition profile, selective GSK-3 inhibitors like C91 may provide similar effects to BIA with reduced off-target toxicity. Inhibition of GSK-3 represents a promising strategy to improve DMG therapy by limiting tumor cell migration and motility while enhancing drug delivery through modulation of the BBB.
- Notes:
- Thesis (Ph. D.)--Brown University, 2026
Citation
Clark, Jasmine Sharee,
"Breaking Barriers: Evaluating GSK-3 Inhibition as a Dual Therapeutic Strategy in Diffuse Midline Glioma Models"
(2026).
Molecular Pharmacology, Physiology, and Biotechnology.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:4smmag7x/
