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

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 () and Bryan W. Day ()
Additional contact information
Yuchen Li: QIMR Berghofer Medical Research Institute
Chaemin Lim: University of North Carolina at Chapel Hill
Taylor Dismuke: University of North Carolina School of Medicine
Daniel S. Malawsky: University of North Carolina School of Medicine
Sho Oasa: Karolinska Institutet
Zara C. Bruce: QIMR Berghofer Medical Research Institute
Carolin Offenhäuser: QIMR Berghofer Medical Research Institute
Ulrich Baumgartner: QIMR Berghofer Medical Research Institute
Rochelle C. J. D’Souza: QIMR Berghofer Medical Research Institute
Stacey L. Edwards: QIMR Berghofer Medical Research Institute
Juliet D. French: QIMR Berghofer Medical Research Institute
Lucy S. H. Ock: QIMR Berghofer Medical Research Institute
Sneha Nair: QIMR Berghofer Medical Research Institute
Haran Sivakumaran: QIMR Berghofer Medical Research Institute
Lachlan Harris: QIMR Berghofer Medical Research Institute
Andrey P. Tikunov: University of North Carolina School of Medicine
Duhyeong Hwang: University of North Carolina at Chapel Hill
Coral Del Mar Alicea Pauneto: University of North Carolina School of Medicine
Mellissa Maybury: The University of Queensland
Timothy Hassall: The University of Queensland
Brandon Wainwright: The University of Queensland
Santosh Kesari: Inc
Gregory Stein: Telethon Kids Institute
Michael Piper: The University of Queensland
Terrance G. Johns: Telethon Kids Institute
Marina Sokolsky-Papkov: University of North Carolina at Chapel Hill
Lars Terenius: Karolinska Institutet
Vladana Vukojević: Karolinska Institutet
Leon F. McSwain: Emory University
Timothy R. Gershon: Emory University
Bryan W. Day: QIMR Berghofer Medical Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-024-54861-3

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