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

Author

Listed:
  • Yuchen Li

    (QIMR Berghofer Medical Research Institute
    The University of Queensland)

  • Chaemin Lim

    (University of North Carolina at Chapel Hill
    CHA University)

  • Taylor Dismuke

    (University of North Carolina School of Medicine)

  • Daniel S. Malawsky

    (University of North Carolina School of Medicine
    Wellcome Sanger Institute)

  • 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
    The University of Queensland
    Queensland University of Technology)

  • Rochelle C. J. D’Souza

    (QIMR Berghofer Medical Research Institute
    The University of Queensland)

  • 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
    The University of Queensland)

  • Andrey P. Tikunov

    (University of North Carolina School of Medicine
    Emory University)

  • Duhyeong Hwang

    (University of North Carolina at Chapel Hill
    Keimyung University)

  • Coral Del Mar Alicea Pauneto

    (University of North Carolina School of Medicine
    University of North Carolina School of Medicine)

  • Mellissa Maybury

    (The University of Queensland)

  • Timothy Hassall

    (The University of Queensland
    Children’s Health Queensland Hospital & Health Service)

  • 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
    Emory University)

  • Bryan W. Day

    (QIMR Berghofer Medical Research Institute
    The University of Queensland
    Queensland University of Technology
    UQ Frazer Institute)

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.

Suggested Citation

  • 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 & Lu, 2025. "Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179," Nature Communications, Nature, vol. 16(1), pages 1-23, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-54861-3
    DOI: 10.1038/s41467-024-54861-3
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    References listed on IDEAS

    as
    1. Kinjal Desai & Siyi Wanggou & Erika Luis & Heather Whetstone & Chunying Yu & Robert J. Vanner & Hayden J. Selvadurai & Lilian Lee & Jinchu Vijay & Julia E. Jaramillo & Jerry Fan & Paul Guilhamon & Mic, 2025. "OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
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    Cited by:

    1. Kinjal Desai & Siyi Wanggou & Erika Luis & Heather Whetstone & Chunying Yu & Robert J. Vanner & Hayden J. Selvadurai & Lilian Lee & Jinchu Vijay & Julia E. Jaramillo & Jerry Fan & Paul Guilhamon & Mic, 2025. "OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma," Nature Communications, Nature, vol. 16(1), pages 1-20, December.

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