Preclinical evaluation of ixazomib for high-risk pediatric brain tumors
- 1University of Colorado School of Medicine
Abstract
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. Methods: Ixazomib was tested against cell lines and orthotopic xenograft models of DMG, Myc-amplified medulloblastoma (Myc-MB), and ATRT. RNA sequencing and LC-MS based proteomics were utilized to define functional consequences of ixazomib treatment in these models. Proteasome activity readouts were used to assess ixazomib activity across brain regions and extracranial solid organs. Results: Ixazomib demonstrates consistent cytotoxic effect across high-risk brain tumor models at low nanomolar concentrations. Ixazomib treatment activates proteostatic stress response and apoptosis. Treatment with ixazomib does not demonstrate survival benefit in orthotopic models, however, and pharmacodynamic testing suggests insufficient inhibition of proteasome activity within the CNS compared to extracranial tissues. Conclusions: While many pediatric brain tumor models demonstrate susceptibility to proteasome inhibition, ixazomib may lack sufficient blood-brain barrier penetration to be a translationally viable means of exploiting this vulnerability.
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BibTeX
@misc{janko2026preclinical,
title = {{Preclinical evaluation of ixazomib for high-risk pediatric brain tumors}},
author = {E. Janko and F. M. Walker and M. Slade and E. Danis and P. Bompada and L. Martin Sobral and J. Chapman and S. Bal and G. Link and N. McQuillan and J. M. Mulcahy Levy and A. L. Green and N. A. Dahl},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.11.750478},
url = {https://www.biorxiv.org/content/10.64898/2026.09.11.750478v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Preclinical evaluation of ixazomib for high-risk pediatric brain tumors
AU - E. Janko
AU - F. M. Walker
AU - M. Slade
AU - E. Danis
AU - P. Bompada
AU - L. Martin Sobral
AU - J. Chapman
AU - S. Bal
AU - G. Link
AU - N. McQuillan
AU - J. M. Mulcahy Levy
AU - A. L. Green
AU - N. A. Dahl
PY - 2026
DA - 2026/09/11
PB - bioRxiv
DO - 10.64898/2026.09.11.750478
UR - https://www.biorxiv.org/content/10.64898/2026.09.11.750478v1
AB - 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. Methods: Ixazomib was tested against cell lines and orthotopic xenograft models of DMG, Myc-amplified medulloblastoma (Myc-MB), and ATRT. RNA sequencing and LC-MS based proteomics were utilized to define functional consequences of ixazomib treatment in these models. Proteasome activity readouts were used to assess ixazomib activity across brain regions and extracranial solid organs. Results: Ixazomib demonstrates consistent cytotoxic effect across high-risk brain tumor models at low nanomolar concentrations. Ixazomib treatment activates proteostatic stress response and apoptosis. Treatment with ixazomib does not demonstrate survival benefit in orthotopic models, however, and pharmacodynamic testing suggests insufficient inhibition of proteasome activity within the CNS compared to extracranial tissues. Conclusions: While many pediatric brain tumor models demonstrate susceptibility to proteasome inhibition, ixazomib may lack sufficient blood-brain barrier penetration to be a translationally viable means of exploiting this vulnerability.
ER -