Abstract
A
bstract
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.
K
ey
P
oints
Ixazomib is effective against Myc-MB, ATRT and DMG tumors
in vitro
Ixazomib treatment does not prolong survival in orthotopic models
Ixazomib may fail to achieve sufficient suppression of proteasome activity within the CNS
I
mportance of
S
tudy
Many high-risk subsets of pediatric brain tumors continue to experience unsatisfactory clinical outcomes under current treatment regimens. Previous research has shown many of these diseases to be responsive to proteasome inhibition, and recent phase 0 data in glioblastoma has suggested that the agent ixazomib may achieve meaningful concentrations in the CNS following systemic administration. In this study, we test ixazomib across a range of pediatric brain tumor models. Using transcriptomic and proteomic approaches, we find that ixazomib effectively triggers proteostatic stress responses and induces apoptosis across a histologic range of CNS malignancies. Orthotopic models fail to demonstrate a survival benefit from ixazomib treatment, however, and pharmacodynamic readouts suggest limited proteasome suppression within the CNS. These findings caution further translational efforts for this agent in children with primary brain tumors.