. 2025 Mar 7;27(3):795-810.

doi: 10.1093/neuonc/noae215.

Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma

Matthew Gallitto^{1

2}, Xu Zhang³, Genesis De Los Santos², Hong-Jian Wei^{4

1

2}, Ester Calvo Fernández^{5

6

7

8}, Shoufu Duan^{3

9}, Geoffrey Sedor^{1

2}, Nina Yoh¹⁰, Danae Kokossis², J Carlos Angel^{11

12}, Yi-Fang Wang², Erin White⁶, Connor J Kinslow^{1

2}, Xander Berg², Lorenzo Tomassoni^{6

13}, Fereshteh Zandkarimi¹⁴, Iok In Christine Chio³, Peter Canoll^{5

10}, Jeffrey N Bruce¹⁰, Neil A Feldstein¹⁰, Robyn D Gartrell^{15

16}, Simon K Cheng^{1

2}, James H Garvin¹⁵, Stergios Zacharoulis¹⁵, Robert J Wechsler-Reya^{17

1}, Jovana Pavisic^{15

18}, Andrea Califano^{19

20

21

12

6

1}, Zhiguo Zhang³, Cheng-Chia Wu^{4

22

23

24

25}

Affiliations

¹ Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian, New York, New York, USA.
² Department of Radiation Oncology, Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian, New York, New York, USA.
³ Department of Genetics and Development, Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA.
⁴ Fralin Biomedical Research Institute, Virginia Polytechnic Institute and State University, Roanoke, 24016, USA.
⁵ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA.
⁶ Department of Systems Biology, Columbia University Irving Medical Center, New York, New York, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁸ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁹ State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
¹⁰ Department of Neurological Surgery, Columbia University Irving Medical Center, New York, New York, USA.
¹¹ Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, New York, USA.
¹² Department of Biomedical Informatics, Columbia University, New York, New York, USA.
¹³ DarwinHealth Inc., New York, NYUSA.
¹⁴ Department of Chemistry, Columbia University, New York, New York, USA.
¹⁵ Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA.
¹⁶ Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁷ Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
¹⁸ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁹ Chan Zuckerberg Biohub New York, New York, New York, USA.
²⁰ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.
²¹ Department of Medicine, Columbia University, New York, New YorkUSA.
²² Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, 24016, USA.
²³ Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, 24061, USA.
²⁴ The Brain Tumor Institute, Children's National Hospital, Washington, 20010, USA.
²⁵ Center for Cancer and Immunology Research, Children's National Hospital, Washington, 20010, USA.

PMID: 39394920
PMCID: PMC11889722 (available on 2025-10-12)
DOI: 10.1093/neuonc/noae215

Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma

Matthew Gallitto et al. Neuro Oncol. 2025.

. 2025 Mar 7;27(3):795-810.

doi: 10.1093/neuonc/noae215.

Authors

Affiliations

¹ Herbert Irving Comprehensive Cancer Center, Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian, New York, New York, USA.
² Department of Radiation Oncology, Columbia University Vagelos College of Physicians and Surgeons and NewYork-Presbyterian, New York, New York, USA.
³ Department of Genetics and Development, Institute for Cancer Genetics, Columbia University Irving Medical Center, New York, New York, USA.
⁴ Fralin Biomedical Research Institute, Virginia Polytechnic Institute and State University, Roanoke, 24016, USA.
⁵ Department of Pathology and Cell Biology, Columbia University Irving Medical Center, New York, New York, USA.
⁶ Department of Systems Biology, Columbia University Irving Medical Center, New York, New York, USA.
⁷ Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
⁸ Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
⁹ State Key Laboratory of Mycology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, 100101, China.
¹⁰ Department of Neurological Surgery, Columbia University Irving Medical Center, New York, New York, USA.
¹¹ Department of Molecular Pharmacology and Therapeutics, Columbia University, New York, New York, USA.
¹² Department of Biomedical Informatics, Columbia University, New York, New York, USA.
¹³ DarwinHealth Inc., New York, NYUSA.
¹⁴ Department of Chemistry, Columbia University, New York, New York, USA.
¹⁵ Department of Pediatrics, Columbia University Irving Medical Center, New York, New York, USA.
¹⁶ Division of Pediatric Oncology, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁷ Department of Neurology, Columbia University Irving Medical Center, New York, New York, USA.
¹⁸ Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
¹⁹ Chan Zuckerberg Biohub New York, New York, New York, USA.
²⁰ Department of Biochemistry and Molecular Biophysics, Columbia University, New York, New York, USA.
²¹ Department of Medicine, Columbia University, New York, New YorkUSA.
²² Department of Internal Medicine, Virginia Tech Carilion School of Medicine, Roanoke, 24016, USA.
²³ Department of Biomedical Engineering and Mechanics, Virginia Polytechnic Institute and State University, Blacksburg, 24061, USA.
²⁴ The Brain Tumor Institute, Children's National Hospital, Washington, 20010, USA.
²⁵ Center for Cancer and Immunology Research, Children's National Hospital, Washington, 20010, USA.

PMID: 39394920
PMCID: PMC11889722 (available on 2025-10-12)
DOI: 10.1093/neuonc/noae215

Abstract

Background: Diffuse midline glioma (DMG) is the most aggressive primary brain tumor in children. All previous studies examining the role of systemic agents have failed to demonstrate a survival benefit; the only standard of care is radiation therapy (RT). Successful implementation of radiosensitization strategies in DMG remains an essential and promising avenue of investigation. We explore the use of Napabucasin, an NAD(P)H quinone dehydrogenase 1 (NQO1)-bioactivatable reactive oxygen species (ROS)-inducer, as a potential therapeutic radiosensitizer in DMG.

Methods: In this study, we conduct in vitro and in vivo assays using patient-derived DMG cultures to elucidate the mechanism of action of Napabucasin and its radiosensitizing properties. As penetration of systemic therapy through the blood-brain barrier (BBB) is a significant limitation to the success of DMG therapies, we explore focused ultrasound (FUS) and convection-enhanced delivery (CED) to overcome the BBB and maximize therapeutic efficacy.

Results: Napabucasin is a potent ROS-inducer and radiosensitizer in DMG, and treatment-mediated ROS production and cytotoxicity are dependent on NQO1. In subcutaneous xenograft models, combination therapy with RT improves local control. After optimizing targeted drug delivery using CED in an orthotopic mouse model, we establish the novel feasibility and survival benefit of CED of Napabucasin concurrent with RT.

Conclusions: As nearly all DMG patients will receive RT as part of their treatment course, our validation of the efficacy of radiosensitizing therapy using CED to prolong survival in DMG opens the door for exciting novel studies of alternative radiosensitization strategies in this devastating disease while overcoming limitations of the BBB.

Keywords: blood-brain barrier; convection-enhanced drug delivery; diffuse midline glioma; focused ultrasound; radiosensitization.

© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.

PubMed Disclaimer

Conflict of interest statement

Dr. Califano is founder, equity holder, and consultant of DarwinHealth Inc., a company that has licensed some of the algorithms used in this manuscript from Columbia University. Columbia University is also an equity holder in DarwinHealth Inc. US patent number 10,790,040 has been awarded related to this work, and has been assigned to Columbia University with Dr. Califano as an inventor. Lorenzo Tomassoni is an employee of DarwinHealth Inc.

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Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma

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Targeted delivery of napabucasin with radiotherapy improves outcomes in diffuse midline glioma

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