ArticleNature communications2025
Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179.
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21 citing papers in PubMed.
- From developmental origins to relapse: molecular and therapeutic insights in medulloblastoma.Child's nervous system : ChNS : official journal of the International Society for Pediatric Neurosurgery · 2026Review
- Organoids as next-generation models for investigating intracranial tumours.Molecular brain · 2026Review
- Purinergic signaling promotes gliomagenesis through nuclear calcium transients.bioRxiv : the preprint server for biology · 2026Article
- Myeloid compartment reprogramming through nanoparticle-delivered resiquimod blocks paracrine growth support and activates phagocytosis to slow tumor progression in endogenous mouse medulloblastoma and diffuse midline glioma models.bioRxiv : the preprint server for biology · 2026Article
- Endothelial-specific Ezh2 deficiency exacerbates blood-brain barrier dysfunction and neuroinflammation in sepsis-associated encephalopathy.Journal of neuroinflammation · 2026Article
- Oligodendrocyte transcription factor 2 orchestrates glioblastoma immune evasion by suppressing CXCL10 and CD8+ T cell activation.The Journal of clinical investigation · 2026Article
- Recapitulating the tumour microenvironment: advancing personalised radiation therapy through organoid technology.Journal of experimental & clinical cancer research : CR · 2026Review
- Targeting Pediatric Glioblastomas by Combining OLIG2 Inhibitor CT-179 with Fractionated Radiation in a Panel of Patient-Derived Orthotopic Xenograft Mouse Models.International journal of molecular sciences · 2026Article
- Medulloblastoma stem cell programs: Molecular roadmaps of disease progression.Developmental cell · 2026Review
- Drug and single-cell gene expression integration identifies sensitive and resistant glioblastoma cell populations.Nature communications · 2026Article
- Medulloblastoma: Current Standard of Care and Future Treatment Opportunities.Paediatric drugs · 2026Review
- Relative biological effectiveness and neural stem cell fate in carbon ion-irradiated human brain organoids.Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology · 2026Article
- Advancing Medulloblastoma Treatment: Molecular Mechanisms, Drug Repurposing, and Precision Therapies.Molecular diagnosis & therapy · 2026Review
- Epigenetic Regulation of OLIG2 in Glioblastoma: Mechanisms and Therapeutic Targets to Combat Treatment Resistance.Journal of molecular neuroscience : MN · 2025Review
- Advancing Medulloblastoma Therapy in Pediatrics: Integrative Molecular Classification and Emerging Treatments.Brain sciences · 2025Review
- Celebrating 50 years of fluorescence correlation spectroscopy (FCS): Advancing live-cell massively parallel FCS studies with photostable GFPs, mStayGold and StayGold/E138D.Biochimica et biophysica acta. General subjects · 2025Article
- OLIG2 mediates a rare targetable stem cell fate transition in sonic hedgehog medulloblastoma.Nature communications · 2025Article
- Pediatric metastatic extracranial high-grade glioma: A case report and literature review.Neuro-oncology practice · 2025Article
- Personalising glioblastoma medicine: explant organoid applications, challenges and future perspectives.Acta neuropathologica communications · 2025Review
- Medulloblastoma: biology and immunotherapy.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
31 authors.
Yuchen Li *QIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.ORCID http://orcid.org/0000-0001-7091-3073
Chaemin Lim *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.
Taylor Dismuke *Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
Daniel S MalawskyDepartment of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.ORCID http://orcid.org/0000-0003-4421-8688
Sho OasaDepartment of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, 17176, Stockholm, Sweden.ORCID http://orcid.org/0000-0003-3800-590X
Zara C BruceQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Carolin OffenhäuserQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.ORCID http://orcid.org/0000-0003-2518-1779
Ulrich BaumgartnerQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.ORCID http://orcid.org/0000-0001-8170-0567
Rochelle C J D'SouzaQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Stacey L EdwardsQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.ORCID http://orcid.org/0000-0001-7428-4139
Juliet D FrenchQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.ORCID http://orcid.org/0000-0002-9770-0198
Lucy S H OckQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.ORCID http://orcid.org/0000-0002-1680-3954
Sneha NairQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.
Haran SivakumaranQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.ORCID http://orcid.org/0000-0002-4691-4989
Lachlan HarrisQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia.ORCID http://orcid.org/0000-0002-7820-0921
Andrey P TikunovDepartment of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
Duhyeong HwangCenter 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.
Coral Del Mar Alicea PaunetoDepartment of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC, 27599, USA.
Mellissa MayburyChild Health Research Centre, The University of Queensland, Brisbane, QLD, 4101, Australia.
Timothy HassallThe Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia.
Brandon WainwrightThe Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia.
Santosh KesariCurtana Pharmaceuticals, Inc, Austin, TX, 78756, USA.ORCID http://orcid.org/0000-0003-3772-6000
Gregory SteinTelethon Kids Institute, Perth, WA, 6009, Australia.ORCID http://orcid.org/0000-0002-3588-8834
Michael PiperThe Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4072, Australia.
Terrance G JohnsTelethon Kids Institute, Perth, WA, 6009, Australia.ORCID http://orcid.org/0000-0002-8874-4543
Marina Sokolsky-PapkovCenter 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.ORCID http://orcid.org/0000-0002-3462-9013
Lars TereniusDepartment of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, 17176, Stockholm, Sweden.ORCID http://orcid.org/0000-0003-2880-9576
Vladana VukojevićDepartment of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska Institutet, 17176, Stockholm, Sweden.ORCID http://orcid.org/0000-0003-0873-5653
Leon F McSwainDepartment of Pediatrics, Emory University, Atlanta, GA, 30323, USA.
Timothy R GershonDepartment of Pediatrics, Emory University, Atlanta, GA, 30323, USA. timothy.gershon@emory.edu.ORCID http://orcid.org/0000-0001-7034-6400
Bryan W DayQIMR Berghofer Medical Research Institute, Brisbane, QLD, 4006, Australia. bryan.day@qimrberghofer.edu.au.
Funding
Transgenic Mouse FacilityP30CA033572 · NCI · CITY OF HOPE/BECKMAN RESEARCH INSTITUTE · PI STANLEY R. HAMILTON · 1985 to 2026
$86.3MCANCER CELL BIOLOGY TRAINING PROGRAMT32CA071341 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI CHANNING J. DER, Yuliya Pylayeva-Gupta · 1996 to 2026
$5.0MBcl-xL-regulated apoptosis in cerebellar development and medulloblastoma treatmentR01NS102627 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI GERSHON, TIMOTHY · 2018 to 2022
$1.8MDefining the crucial role of MAGOH in cerebellar development and the potential for targeting the EJC in medulloblastoma treatmentR01NS106227 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI GERSHON, TIMOTHY · 2018 to 2023
$1.7MGlycolytic regulation of cerebellar development and medulloblastoma tumorigenesisR01NS088219 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI GERSHON, TIMOTHY · 2015 to 2019
$1.6MImproving CDK 4/6 inhibition in the treatment of medulloblastomaF31NS120459 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DISMUKE, TAYLOR YVETTE · 2020 to 2022
$59kNCI NIH HHS P30 CA033572NCI NIH HHS T32 CA071341NINDS NIH HHS F31 NS120459NINDS NIH HHS R01 NS088219NINDS NIH HHS R01 NS102627NINDS NIH HHS R01 NS106227U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01NS088219U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01NS102627U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS) R01NS106227
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.
Indexed as
Cerebellar NeoplasmsHedgehog ProteinsMedulloblastomaNeoplasm Recurrence, LocalOligodendrocyte Transcription Factor 2AnimalsApoptosisCell DifferentiationCell Line, TumorCell ProliferationCyclin-Dependent Kinase 4HumansMiceNeoplastic Stem CellsPiperazinesPyridinesCyclin-Dependent Kinase 4Hedgehog ProteinsOLIG2 protein, humanOligodendrocyte Transcription Factor 2palbociclibPiperazinesPyridinesSHH protein, human
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