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

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.

Authors

Institutions

Publication Details

Journal
Nature Communications
Published
2025-02-04
DOI
https://doi.org/10.1038/s41467-024-54861-3
Citations
12
Primary Topic
Hedgehog Signaling Pathway Studies
Type
article
Field-Weighted Citation Impact
9.67

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Sho Oasa, Mellissa Maybury, Daniel Shiloh Malawsky, Brandon J. Wainwright et al.
12 citations
Nature Communications
Hedgehog Signaling Pathway Studies
9.67
article

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

Sho Oasa, Mellissa Maybury, Daniel Shiloh Malawsky, Brandon J. Wainwright, Rochelle C. J. D’Souza, Lars Terenius, Marina Sokolsky‐Papkov, Terrance G. Johns, Vladana Vukojević, Carolin Offenhäuser, Zara C. Bruce, Taylor Dismuke, Coral del Mar Alicea Pauneto, Gregory Stein, Leon McSwain, Ulrich Baumgartner, Juliet D. French, Tim Hassall, Duhyeong Hwang, Santosh Kesari, Yuchen Li, Stacey L. Edwards, Bryan W. Day, Michael Piper, Timothy R. Gershon, Andrey P. Tikunov, Chaemin Lim, Lachlan Harris, Lucy S. H. Ock, Haran Sivakumaran, Sneha Nair
article en
12 citations

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.

Nature CommunicationsVol. 16(1)
University of North Carolina at Chapel Hill (US), Emory University (US), Queensland University of Technology (AU), The University of Queensland (AU), The Kids Research Institute Australia (AU), QIMR Berghofer Medical Research Institute (AU), Wellcome Sanger Institute (GB), Karolinska Institutet (SE), Children’s Health Queensland Hospital and Health Service (AU), Children's Cancer Institute Australia (AU), CHA University (KR), Children's Center (US), Children's Health Queensland Hospital and Health Service (AU), Keimyung University (KR)
Emory University, Children's Hospital Foundation, QIMR Berghofer Medical Research Institute, National Research Foundation, Queensland University of Technology, University of Queensland, Keimyung University, National Research Foundation of Korea, Karolinska Institutet, CHA University, Ministry of Science and ICT, South Korea, University of North Carolina at Chapel Hill, National Health and Medical Research Council, National Institute of Neurological Disorders and Stroke, School of Medicine, University of North Carolina at Chapel Hill, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill
Zero hunger
Openalex Percentile: Top 2%
Hedgehog Signaling Pathway Studies
9.67
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.