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<p>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 <i>Cdk4</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月4日

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  • 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

摘要

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.