Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179 PMID: 39904981

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2025 Feb 4;16(1):1091. doi: 10.1038/s41467-024-54861-3.

Yuchen Li ^# ¹ ² , Chaemin Lim ^# ³ ⁴ , Taylor Dismuke ^# ⁵ , Daniel S Malawsky ⁵ ⁶ , Sho Oasa ⁷ , Zara C Bruce ¹ , Carolin Offenhäuser ¹ , Ulrich Baumgartner ¹ ² ⁸ , Rochelle C J D'Souza ¹ ² , Stacey L Edwards ¹ , Juliet D French ¹ , Lucy S H Ock ¹ , Sneha Nair ¹ , Haran Sivakumaran ¹ , Lachlan Harris ¹ ² , Andrey P Tikunov ⁵ ⁹ , Duhyeong Hwang ³ ¹⁰ , Coral Del Mar Alicea Pauneto ⁵ ¹¹ , Mellissa Maybury ¹² , Timothy Hassall ² ¹³ , Brandon Wainwright ² , Santosh Kesari ¹⁴ , Gregory Stein ¹⁵ , Michael Piper ² , Terrance G Johns ¹⁵ , Marina Sokolsky-Papkov ³ , Lars Terenius ⁷ , Vladana Vukojević ⁷ , Leon F McSwain ⁹ , Timothy R Gershon ¹⁶ ¹⁷ , Bryan W Day ¹⁸ ¹⁹ ²⁰ ²¹

Affiliations

1. QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
2. The Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia.
3. Center for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
4. College of Pharmacy, CHA University, 335 PangyoPangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13488, Republic of Korea.
5. Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
6. Wellcome Sanger Institute, Hinxton, Cambridgeshire, UK.
7. Department of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, 17176, Stockholm, Sweden.
8. School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4072, Australia.
9. Department of Pediatrics, Emory University, Atlanta, GA, 30323, USA.
10. College of Pharmacy, Keimyung University, Daegu, 42601, Republic of Korea.
11. Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
12. Child Health Research Centre, The University of Queensland, Brisbane, QLD, 4101, Australia.
13. Oncology Service, Queensland Children's Hospital, Children's Health Queensland Hospital & Health Service, Brisbane, QLD, 4101, Australia.
14. Curtana Pharmaceuticals, Inc, Austin, TX, 78756, USA.
15. Telethon Kids Institute, Perth, WA, 6009, Australia.
16. Department of Pediatrics, Emory University, Atlanta, GA, 30323, USA. [email protected].
17. Children's Center for Neurosciences Research, Emory University, Atlanta, GA, 30323, USA. [email protected].
18. QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. [email protected].
19. The Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia. [email protected].
20. School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4072, Australia. [email protected].
21. Children's Brain Cancer Centre, UQ Frazer Institute, Brisbane, QLD, 4102, Australia. [email protected].
# Contributed equally.

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.