Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179

Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179

Abstract OLIG2-expressing tumor stem cells have been shown to drive recurrence in Sonic Hedgehog (SHH)-subgroup medulloblastoma (MB) and patients urgently need specific therapies to target this tumor cell population. Here, we investigate the therapeutic potential of the brain-penetrant orally bioava...

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Main Authors: Yuchen Li, Chaemin Lim, Taylor Dismuke, Daniel S. Malawsky, Sho Oasa, Zara C. Bruce, Carolin Offenhäuser, Ulrich Baumgartner, Rochelle C. J. D’Souza, Stacey L. Edwards, Juliet D. French, Lucy S. H. Ock, Sneha Nair, Haran Sivakumaran, Lachlan Harris, Andrey P. Tikunov, Duhyeong Hwang, Coral Del Mar Alicea Pauneto, Mellissa Maybury, Timothy Hassall, Brandon Wainwright, Santosh Kesari, Gregory Stein, Michael Piper, Terrance G. Johns, Marina Sokolsky-Papkov, Lars Terenius, Vladana Vukojević, Leon F. McSwain, Timothy R. Gershon, Bryan W. Day
Format: Article
Language:English
Published: Nature Portfolio 2025-02-01
Series:Nature Communications
Online Access:https://doi.org/10.1038/s41467-024-54861-3
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Summary:Abstract OLIG2-expressing tumor stem cells have been shown to drive recurrence in Sonic Hedgehog (SHH)-subgroup medulloblastoma (MB) and patients urgently need specific therapies to target this tumor cell population. Here, we investigate the therapeutic potential of the brain-penetrant orally bioavailable, OLIG2 inhibitor CT-179, using SHH-MB explant organoids, PDX and GEM SHH-MB models. We find that CT-179 disrupts OLIG2 dimerization, phosphorylation and DNA binding and alters tumor cell-cycle kinetics, increasing differentiation and apoptosis. CT-179 prolongs survival in SHH-MB PDX and GEM models and potentiates radiotherapy (RT) in vivo. Single cell transcriptomic studies (scRNA-seq) confirm that CT-179 increases differentiation and implicate Cdk4 up-regulation in maintaining proliferation during treatment. Consistent with CDK4 mediating CT-179 resistance, CT-179 combines effectively with the CDK4/6 inhibitor palbociclib, further prolonging survival in vivo. These data support therapeutic targeting of OLIG2+ tumor stem cells in regimens for SHH-driven MB, to improve response, delay recurrence and ultimately improve MB patient outcomes.
ISSN:2041-1723

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