Preclinical evaluation of ixazomib for high-risk pediatric brain tumors

Background

Many of the highest risk pediatric brain cancers continue to experience poor clinical outcomes despite intensification of current multimodal therapy. Proteasome inhibition has shown preclinical promise across a range of cancer models including diffuse midline glioma (DMG), medulloblastoma, and atypical teratoid / rhabdoid tumors (ATRT), though clinically viable agents have been limited. Recent studies in adults with glioblastoma suggest that ixazomib, a second-generation proteasome inhibitor, might achieve therapeutic concentrations in the CNS, presenting the opportunity that a CNS penetrant proteasome inhibitor might be similarly leveraged for benefit in childhood brain cancers.