2. Academic Validation
  3. Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179

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

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. timothy.gershon@emory.edu.
  • 17 Children's Center for Neurosciences Research, Emory University, Atlanta, GA, 30323, USA. timothy.gershon@emory.edu.
  • 18 QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. bryan.day@qimrberghofer.edu.au.
  • 19 The Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia. bryan.day@qimrberghofer.edu.au.
  • 20 School of Biomedical Sciences, Queensland University of Technology, Brisbane, QLD, 4072, Australia. bryan.day@qimrberghofer.edu.au.
  • 21 Children's Brain Cancer Centre, UQ Frazer Institute, Brisbane, QLD, 4102, Australia. bryan.day@qimrberghofer.edu.au.
  • # Contributed equally.
PMID: 39904981 DOI: 10.1038/s41467-024-54861-3
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.

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