Targeting OLIG2 increases therapeutic responses in SHH medulloblastoma mouse models and patient-derived medulloblastoma organoids
Li, Y.; Dismuke, T.; Lim, C.; Bruce, Z. C.; Offenhauser, C.; Baumgartner, U.; Maybury, M.; DSouza, R. C. J.; Hassall, T.; Wainwright, B.; Stein, G.; Piper, M.; Johns, T. G.; Sokolsky-Papkov, M.; Gershon, T. R.; Day, B. W.
Show abstract
Recurrence after therapy is the primary life-threatening complication of medulloblastoma. In Sonic Hedgehog (SHH)-subgroup medulloblastoma, OLIG2-expressing tumour stem cells are crucial to recurrence. We investigated the potential of the small-molecule OLIG2 inhibitor CT-179 to decrease recurrence in patient-derived organoids, mice genetically-engineered to develop SHH-driven MB, and mice with MB patient-derived xenograft (PDX) tumours. We found that OLIG2 mRNA significantly correlated with poor survival in patients with SHH-MB, but not other subgroups. CT-179 rapidly downregulated OLIG2 protein in vitro and displayed nanomolar IC50 values. CT-179 arrested MB cells at G2/M, with degradation of cyclin B1 and phospho-CDK1 inducing apoptosis. In vivo CT-179 induced similar cell cycle changes in MBs in Smo-mutant mice and significantly increased mouse survival. In both MB organoids and mouse models, CT-179 combined with radiotherapy showed greater efficacy than either treatment alone. These data highlight the potential for OLIG2-targeted therapy to improve MB outcomes by targeting recurrent disease.
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