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Peer-reviewedCC BY 4.0Cell Reports Medicine

A standardized patient-derived glioblastoma organoid platform for evaluating radiotherapy efficacy and overcoming resistance

  • Xin Wang1
  • Yusha Sun2
  • Prithvi Sinha3
  • Ruiying Su3
  • Daniel Y. Zhang4
  • Kristen H. Park2
  • Yao Fu5
  • Weifan Dong1
  • Zhijian Zhang1
  • Qing Wang6
  • Daniel H. Geschwind6
  • Riki Kawaguchi6
12 more authors
  • Emily Ling-Lin Pai7
  • Maria A. Gubbiotti7
  • Robert Colbourn7
  • Nduka M. Amankulor4
  • Jay F. Dorsey3,8
  • MacLean P. Nasrallah7,8
  • Stephen J. Bagley8,9
  • Zev A. Binder4,8,10
  • Donald M. O’Rourke4,8,10,11
  • Yi Fan3,8
  • Guo-li Ming1,12,13,14
  • Hongjun Song1,4,8,12,15
15 affiliations
  1. 1Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  2. 2Neuroscience Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  3. 3Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA, USA
  4. 4Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  5. 5Department of Biology, School of Arts and Sciences, University of Pennsylvania, Philadelphia, PA, USA
  6. 6Program in Neurogenetics, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA
  7. 7Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  8. 8Glioblastoma Translational Center of Excellence, The Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
  9. 9Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  10. 10Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  11. 11Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  12. 12Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, PA, USA
  13. 13Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  14. 14Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  15. 15The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Abstract

Patient-derived glioblastoma (GBM) organoids (GBOs) maintain characteristics of their original tumors; however, they have not been widely applied to systematically assess therapy responses at scale or elucidate mechanisms underlying treatment resistance. Here, we develop a standardized reaggregated GBO (rGBO) platform for scalable, quantitative evaluation of radiation responses across 48 patients with GBM. Radiation responses in rGBOs correlate with the survival duration of corresponding patients treated with standard-of-care radiotherapy. Transcriptomic analyses identify gene signatures associated with radiosensitivity and radioresistance. Connectivity mapping with perturbational datasets identifies a panel of compounds with potential for reducing radioresistant and enhancing radiosensitive signatures. Subsequent testing demonstrates that inhibitors of bromodomain and extraterminal (BET) family proteins enhance radiotherapy efficacy in GBO and xenograft models by downregulating the radioresistant signature. Together, our study highlights the potential of rGBOs for standardizing therapeutic screening, evaluating patient-specific responses, identifying associated molecular features, and developing strategies to overcome treatment resistance.

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Cite

BibTeXRIS
BibTeX
@article{wang2026standardized,
  title = {{A standardized patient-derived glioblastoma organoid platform for evaluating radiotherapy efficacy and overcoming resistance}},
  author = {Xin Wang and Yusha Sun and Prithvi Sinha and Ruiying Su and Daniel Y. Zhang and Kristen H. Park and Yao Fu and Weifan Dong and Zhijian Zhang and Qing Wang and Daniel H. Geschwind and Riki Kawaguchi and Emily Ling-Lin Pai and Maria A. Gubbiotti and Robert Colbourn and Nduka M. Amankulor and Jay F. Dorsey and MacLean P. Nasrallah and Stephen J. Bagley and Zev A. Binder and Donald M. O’Rourke and Yi Fan and Guo-li Ming and Hongjun Song},
  journal = {Cell Reports Medicine},
  year = {2026},
  month = oct,
  doi = {10.1016/j.xcrm.2026.103095},
  url = {https://doi.org/10.1016/j.xcrm.2026.103095},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - A standardized patient-derived glioblastoma organoid platform for evaluating radiotherapy efficacy and overcoming resistance
AU  - Xin Wang
AU  - Yusha Sun
AU  - Prithvi Sinha
AU  - Ruiying Su
AU  - Daniel Y. Zhang
AU  - Kristen H. Park
AU  - Yao Fu
AU  - Weifan Dong
AU  - Zhijian Zhang
AU  - Qing Wang
AU  - Daniel H. Geschwind
AU  - Riki Kawaguchi
AU  - Emily Ling-Lin Pai
AU  - Maria A. Gubbiotti
AU  - Robert Colbourn
AU  - Nduka M. Amankulor
AU  - Jay F. Dorsey
AU  - MacLean P. Nasrallah
AU  - Stephen J. Bagley
AU  - Zev A. Binder
AU  - Donald M. O’Rourke
AU  - Yi Fan
AU  - Guo-li Ming
AU  - Hongjun Song
PY  - 2026
DA  - 2026/10/07
JO  - Cell Reports Medicine
DO  - 10.1016/j.xcrm.2026.103095
UR  - https://doi.org/10.1016/j.xcrm.2026.103095
AB  - Patient-derived glioblastoma (GBM) organoids (GBOs) maintain characteristics of their original tumors; however, they have not been widely applied to systematically assess therapy responses at scale or elucidate mechanisms underlying treatment resistance. Here, we develop a standardized reaggregated GBO (rGBO) platform for scalable, quantitative evaluation of radiation responses across 48 patients with GBM. Radiation responses in rGBOs correlate with the survival duration of corresponding patients treated with standard-of-care radiotherapy. Transcriptomic analyses identify gene signatures associated with radiosensitivity and radioresistance. Connectivity mapping with perturbational datasets identifies a panel of compounds with potential for reducing radioresistant and enhancing radiosensitive signatures. Subsequent testing demonstrates that inhibitors of bromodomain and extraterminal (BET) family proteins enhance radiotherapy efficacy in GBO and xenograft models by downregulating the radioresistant signature. Together, our study highlights the potential of rGBOs for standardizing therapeutic screening, evaluating patient-specific responses, identifying associated molecular features, and developing strategies to overcome treatment resistance.
SN  - 2666-3791
ER  -