Nature communications · 2025
Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179.
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Li Yuchen, Lim Chaemin, Dismuke Taylor, Malawsky Daniel S, Oasa Sho, Bruce Zara C, Offenhäuser Carolin, Baumgartner Ulrich, D'Souza Rochelle C J, Edwards Stacey L, French Juliet D, Ock Lucy S H, Nair Sneha, Sivakumaran Haran, Harris Lachlan, Tikunov Andrey P, Hwang Duhyeong, Alicea Pauneto Coral Del Mar, Maybury Mellissa, Hassall Timothy, Wainwright Brandon, Kesari Santosh, Stein Gregory, Piper Michael, Johns Terrance G, Sokolsky-Papkov Marina, Terenius Lars, Vukojević Vladana, McSwain Leon F, Gershon Timothy R, Day Bryan W
Аннотация
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.