Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179
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 bioava...
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Nature Portfolio
2025-02-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-54861-3 |
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| author | Yuchen Li Chaemin Lim Taylor Dismuke Daniel S. Malawsky Sho Oasa Zara C. Bruce Carolin Offenhäuser Ulrich Baumgartner Rochelle C. J. D’Souza Stacey L. Edwards Juliet D. French Lucy S. H. Ock Sneha Nair Haran Sivakumaran Lachlan Harris Andrey P. Tikunov Duhyeong Hwang Coral Del Mar Alicea Pauneto Mellissa Maybury Timothy Hassall Brandon Wainwright Santosh Kesari Gregory Stein Michael Piper Terrance G. Johns Marina Sokolsky-Papkov Lars Terenius Vladana Vukojević Leon F. McSwain Timothy R. Gershon Bryan W. Day |
| author_facet | Yuchen Li Chaemin Lim Taylor Dismuke Daniel S. Malawsky Sho Oasa Zara C. Bruce Carolin Offenhäuser Ulrich Baumgartner Rochelle C. J. D’Souza Stacey L. Edwards Juliet D. French Lucy S. H. Ock Sneha Nair Haran Sivakumaran Lachlan Harris Andrey P. Tikunov Duhyeong Hwang Coral Del Mar Alicea Pauneto Mellissa Maybury Timothy Hassall Brandon Wainwright Santosh Kesari Gregory Stein Michael Piper Terrance G. Johns Marina Sokolsky-Papkov Lars Terenius Vladana Vukojević Leon F. McSwain Timothy R. Gershon Bryan W. Day |
| author_sort | Yuchen Li |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-61daa0c730804b8182b59c81b561bf16 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-61daa0c730804b8182b59c81b561bf162025-02-09T12:45:13ZengNature PortfolioNature Communications2041-17232025-02-0116112310.1038/s41467-024-54861-3Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179Yuchen Li0Chaemin Lim1Taylor Dismuke2Daniel S. Malawsky3Sho Oasa4Zara C. Bruce5Carolin Offenhäuser6Ulrich Baumgartner7Rochelle C. J. D’Souza8Stacey L. Edwards9Juliet D. French10Lucy S. H. Ock11Sneha Nair12Haran Sivakumaran13Lachlan Harris14Andrey P. Tikunov15Duhyeong Hwang16Coral Del Mar Alicea Pauneto17Mellissa Maybury18Timothy Hassall19Brandon Wainwright20Santosh Kesari21Gregory Stein22Michael Piper23Terrance G. Johns24Marina Sokolsky-Papkov25Lars Terenius26Vladana Vukojević27Leon F. McSwain28Timothy R. Gershon29Bryan W. Day30QIMR Berghofer Medical Research InstituteCenter for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel HillDepartment of Neurology, University of North Carolina School of MedicineDepartment of Neurology, University of North Carolina School of MedicineDepartment of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska InstitutetQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteQIMR Berghofer Medical Research InstituteDepartment of Neurology, University of North Carolina School of MedicineCenter for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel HillDepartment of Neurology, University of North Carolina School of MedicineChild Health Research Centre, The University of QueenslandThe Faculty of Medicine, The University of QueenslandThe Faculty of Medicine, The University of QueenslandCurtana Pharmaceuticals, IncTelethon Kids InstituteThe Faculty of Medicine, The University of QueenslandTelethon Kids InstituteCenter for Nanotechnology in Drug Delivery and Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel HillDepartment of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska InstitutetDepartment of Clinical Neuroscience, Center for Molecular Medicine (CMM), Karolinska InstitutetDepartment of Pediatrics, Emory UniversityDepartment of Pediatrics, Emory UniversityQIMR Berghofer Medical Research InstituteAbstract 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.https://doi.org/10.1038/s41467-024-54861-3 |
| spellingShingle | Yuchen Li Chaemin Lim Taylor Dismuke Daniel S. Malawsky Sho Oasa Zara C. Bruce Carolin Offenhäuser Ulrich Baumgartner Rochelle C. J. D’Souza Stacey L. Edwards Juliet D. French Lucy S. H. Ock Sneha Nair Haran Sivakumaran Lachlan Harris Andrey P. Tikunov Duhyeong Hwang Coral Del Mar Alicea Pauneto Mellissa Maybury Timothy Hassall Brandon Wainwright Santosh Kesari Gregory Stein Michael Piper Terrance G. Johns Marina Sokolsky-Papkov Lars Terenius Vladana Vukojević Leon F. McSwain Timothy R. Gershon Bryan W. Day Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179 Nature Communications |
| title | Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179 |
| title_full | Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179 |
| title_fullStr | Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179 |
| title_full_unstemmed | Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179 |
| title_short | Suppressing recurrence in Sonic Hedgehog subgroup medulloblastoma using the OLIG2 inhibitor CT-179 |
| title_sort | suppressing recurrence in sonic hedgehog subgroup medulloblastoma using the olig2 inhibitor ct 179 |
| url | https://doi.org/10.1038/s41467-024-54861-3 |
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