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BMI1 is a therapeutic target in recurrent medulloblastoma

Oncogene volume 38, pages 1702–1716 (2019)Cite this article

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Abstract

Medulloblastoma (MB) is the most frequent malignant pediatric brain tumor, representing 20% of newly diagnosed childhood central nervous system malignancies. Although advances in multimodal therapy yielded a 5-year survivorship of 80%, MB still accounts for the leading cause of childhood cancer mortality. In this work, we describe the epigenetic regulator BMI1 as a novel therapeutic target for the treatment of recurrent human Group 3 MB, a childhood brain tumor for which there is virtually no treatment option beyond palliation. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naive tumors will provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumor. Using a small molecule inhibitor against BMI1, PTC-028, we were able to demonstrate complete ablation of self-renewal of MB stem cells in vitro. When administered to mice xenografted with patient tumors, we observed significant reduction in tumor burden in both local and metastatic compartments and subsequent increased survival, without neurotoxicity. Strikingly, serial in vivo re-transplantation assays demonstrated a marked reduction in tumor initiation ability of recurrent MB cells upon re-transplantation of PTC-028-treated cells into secondary recipient mouse brains. As Group 3 MB is often metastatic and uniformly fatal at recurrence, with no current or planned trials of targeted therapy, an efficacious targeted agent would be rapidly transitioned to clinical trials.

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Acknowledgements

SKS is supported by Canada Research Chair award, and operating grants from Canadian Institutes of Health Research (CIHR), Stem Cell Network, the Ontario Institute for Cancer Research Cancer Stem Cell Program, the Canadian Cancer Society Research Institute, the Cancer Research Society, the Brain Tumor Foundation of Canada, and generous donations from the Box Run Foundation, Team Kelsey, and patients and their families.

Author contributions

DB: conception and design, collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. CV and AAA: conception and design, collection and/or assembly of data, manuscript writing, final approval of manuscript. NG and BM: collection and/or assembly of data, data analysis and interpretation, manuscript writing, final approval of manuscript. RH, XW, S Mahendram, PV, TV, M Subapanditha, M Singh, MMK-S, MQ, NM and AM: data analysis and interpretation, final approval of manuscript. OAA and BY: provision of study material or patients, final approval of manuscript. VR, HF and S Morrissy: collection and/or assembly of data, data analysis and interpretation. LC, NS, RB, WD, JS, MW, Y-CM and C-SL: provision of study material or patients, final approval of manuscript. JMK, KHD: data analysis and interpretation. BD, Y-JC, S Mitra, DK and MDT: conception and design, data analysis and interpretation, final approval of manuscript. TWD: provision of study material or patients, final approval of manuscript. SKS: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript.

Author information

Authors and Affiliations

  1. McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, ON, L8S 4L8, Canada

    David Bakhshinyan, Chitra Venugopal, Ashley A. Adile, Neha Garg, Branavan Manoranjan, Sujeivan Mahendram, Parvez Vora, Thusyanth Vijayakumar, Minomi Subapanditha, Mohini Singh, Michelle Masayo Kameda-Smith, Maleeha Qazi, Nicole McFarlane, Aneet Mann, Brad Doble & Sheila K. Singh

  2. Departments of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4L8, Canada

    David Bakhshinyan, Ashley A. Adile, Branavan Manoranjan, Thusyanth Vijayakumar, Mohini Singh, Michelle Masayo Kameda-Smith, Maleeha Qazi, Brad Doble & Sheila K. Singh

  3. Surgery, Faculty of Health Sciences, McMaster University, Hamilton, ON, L8S 4L8, Canada

    Chitra Venugopal, Neha Garg, Sujeivan Mahendram, Parvez Vora, Minomi Subapanditha, Michelle Masayo Kameda-Smith, Nicole McFarlane, Olufemi A. Ajani, Blake Yarascavitch & Sheila K. Singh

  4. Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada

    Branavan Manoranjan & Sheila K. Singh

  5. Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Robin Hallett & David Kaplan

  6. Developmental & Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Xin Wang, Vijay Ramaswamy & Hamza Farooq

  7. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, M5S 1A1, Canada

    Xin Wang, Hamza Farooq & Michael D. Taylor

  8. Division of Haematology/Oncology, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    Vijay Ramaswamy & Sorana Morrissy

  9. PTC Therapeutics, 100 Corporate Court, South Plainfield, NJ, 07080-2400, USA

    Liangxian Cao, Nadiya Sydorenko, Ramil Baiazitov, Wu Du, Josephine Sheedy, Marla Weetall, Young-Choon Moon, Chang-Sun Lee & Thomas W. Davis

  10. Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, L8S 4L8, Canada

    Jacek M. Kwiecien & Kathleen H. Delaney

  11. Department of Clinical Pathomorphology, Medical University of Lublin, Lublin, Poland

    Jacek M. Kwiecien

  12. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Yoon-Jae Cho & Siddhartha Mitra

  13. Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, 94305, USA

    Yoon-Jae Cho & Siddhartha Mitra

  14. Department of Molecular Genetics, University of Toronto, Toronto, ON, M5G 1X8, Canada

    David Kaplan

  15. Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada

    Michael D. Taylor

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  1. David Bakhshinyan
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Correspondence to Sheila K. Singh.

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Bakhshinyan, D., Venugopal, C., Adile, A.A. et al. BMI1 is a therapeutic target in recurrent medulloblastoma. Oncogene 38, 1702–1716 (2019). https://doi.org/10.1038/s41388-018-0549-9

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