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 ta...
| Authors | Li, Y; Lim, C; Dismuke, T; Malawsky, DS; Oasa, S; Bruce, ZC; Offenhäuser, C; Baumgartner, U; D'Souza, RCJ; Edwards, SL; French, JD; Ock, LSH; Nair, S; Sivakumaran, H; Harris, L; Tikunov, AP; Hwang, D; Alicea Pauneto, CDM; Maybury, M; Hassall, T; Wainwright, B; Kesari, S; Stein, G; Piper, M; Johns, TG; Sokolsky-Papkov, M; Terenius, L; Vukojevic, V; McSwain, LF; Gershon, TR; Day, BW |
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| Journal | Nature Communications |
| Pages | 1091 |
| Volume | 16 |
| Date | 4/03/2025 |
| Grant ID | R01NS102627 | U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); R01NS106227 | U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); R01NS088219 | U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS); F31 NS120459 | NINDS NIH HHS [NS] (United States); R01 NS088219 | NINDS NIH HHS [NS] (United States); R01 NS102627 | NINDS NIH HHS [NS] (United States); R01 NS106227 | NINDS NIH HHS [NS] (United States) |
| Funding Body | |
| URL | http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1038/s41467-024-54861-3 |