Abstract Proteosome inhibition has shown promising preclinical activity in models of pediatric high-grade glioma (PHGG)/diffuse midline gliomas (DMGs), Myc-driven medulloblastoma (Myc-MB), and atypical teratoid/rhabdoid tumors (ATRTs), tumors with diverse biological drivers but uniformly unsatisfactory clinical outcomes. This has been most commonly demonstrated using the agent marizomib owing to its ability to penetrate the blood-brain barrier, but clinical development of this compound is now halted. Ixazomib, an orally available second-generation proteosome inhibitor, has recently been found to achieve CNS penetrance in an adult phase 0 study of glioblastoma, creating an opportunity to leverage this agent for use in high-risk pediatric tumors. Using cell culture model systems of PHGG, DMG, Myc-MB, and ATRT, we observed broad sensitivity to ixazomib in vitro, with low nanomolar IC50 levels. Ixazomib treatment demonstrated synergy with radiation in 8/10 PHGG/DMG models tested. Ixazomib led to an accumulation of ubiquitinylated proteins and induction of apoptosis in tumor models. Transcriptome sequencing and proteomics were utilized to define ixazomib-responsive functional programs. In vivo pharmacodynamic and survival assessments using orthotopic mouse models of PHGG/DMG, Myc-MB, and ATRT are ongoing. Together, these studies evaluate a translationally promising compound for high-risk pediatric brain tumors in need of new therapies.
Janko et al. (2025) studied this question.