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Functionally defined therapeutic targets in diffuse intrinsic pontine glioma

Nature Medicine volume 21, pages 555–559 (2015)Cite this article

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An Erratum to this article was published on 07 July 2015

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Abstract

Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood cancer. We performed a chemical screen in patient-derived DIPG cultures along with RNA-seq analyses and integrated computational modeling to identify potentially effective therapeutic strategies. The multi–histone deacetylase inhibitor panobinostat demonstrated therapeutic efficacy both in vitro and in DIPG orthotopic xenograft models. Combination testing of panobinostat and the histone demethylase inhibitor GSK-J4 revealed that the two had synergistic effects. Together, these data suggest a promising therapeutic strategy for DIPG.

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Figure 1: Functionally defined targets in DIPG therapy.
Figure 2: Panobinostat is a promising therapy for DIPG.

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  • 15 June 2015

     In the version of this article initially published online, there were four typographical errors in the manuscript text. The errors have been corrected in the PDF and HTML versions of this article.

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Acknowledgements

We thank the many children and families who selflessly contributed to this study through tissue donations obtained from surgery or autopsy, and A. Gajjar for his guidance and vision throughout this study. We also thank D. Hargrave, J. Olson and S. Leary for selection of V.2 chemical screen agents. We are grateful for the critical questions and comments by S. Cheetham and N. Nsouli. We also acknowledge important comments by another DIPG Preclinical Consortium member, O. Becher. We thank G. Grant for assistance in developing rodent CED techniques. We thank R. Hashizume and C.D. James (Northwestern University) for use of the SF7761 DIPG cell line. Short-read sequencing was performed by the OHSU Massively Parallel Sequencing Shared Resource. This research is supported by the Lyla Nsouli Foundation, the Children's Oncology Group (COG) Central Nervous System Committee, the DIPG Collaborative (The Cure Starts Now Foundation, Reflections of Grace Foundation, Smiles for Sophie Foundation, Cancer-Free Kids Foundation, Carly's Crusade Foundation, Jeffrey Thomas Hayden Foundation, Soar with Grace Foundation), the Accelerate Brain Cancer Cures Foundation (ABC2), CureSearch for Childhood Cancer, the Team Julian Foundation and the COG Chair's Grant (5UOCA098543). Additional funding support was provided by US National Institutes of Health grant K08NS070926 (to M.M.), Alex's Lemonade Stand Foundation (to M.M. and Y.T.), the McKenna Claire Foundation, the Connor Johnson Memorial Fund, the Dylan Jewett Memorial Fund, the Elizabeth Stein Memorial Fund, the Dylan Frick Memorial Fund, the Abigail Jensen Memorial Fund, the Zoey Ganesh Memorial Fund, the Wayland Villars DIPG Foundation, the Jennifer Kranz Memorial Fund, Unravel Pediatric Cancer, the Virginia & D.K. Ludwig Fund for Cancer Research, the Price Family Charitable Fund, the Matthew Larson Foundation, the Godfrey Family Fund in Memory of Fiona Penelope, the Child Health Research Institute at Stanford, the Anne T. and Robert M. Bass Endowed Faculty Scholarship in Pediatric Cancer and Blood Diseases (all to M.M.), Etoile de Martin (to J.G. and N.T.), Fondation Lemos and Le Défi de Fortunée (to J.G.), the Scott Carter Foundation (to N.E.B.), the Semmy Foundation (to D.G.v.V. and E.H.), the US Department of Defense (to X.-N.L.), National Science Foundation grant CCF0953366 (to R.P.), Marie Curie grant IRG270459 (to M.M.A.); the Spanish Ministry of Health grant PI13/0125 (to M.M.A.), and the St. Baldrick's Foundation and Iron Matt Foundation (both to E.R. and M.H.-C.).

Author information

Author notes

  1. Yujie Tang & Yulun Huang

    Present address: Present addresses: Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Department of Pathophysiology, Shanghai Jiao Tong University School of Medicine, Shanghai, China (Y.T.) and Department of Neurosurgery, The First Affiliated Hospital of Soochow University, Suzhou, China (Y.H.).,

  2. Catherine S Grasso, Yujie Tang and Nathalene Truffaux: These authors contributed equally to this work.

  3. Charles Keller, Ranadip Pal, Jacques Grill and Michelle Monje: These authors jointly directed this work.

Authors and Affiliations

  1. Department of Molecular and Medical Genetics, Center for Spatial Systems Biomedicine, Oregon Health & Science University (OHSU), Portland, Oregon, USA

    Catherine S Grasso, Michael J Quist, Matthew N Svalina, Nicholas Wang & Paul T Spellman

  2. Department of Neurology, Stanford University, Stanford, California, USA

    Yujie Tang, Lining Liu, Pamelyn J Woo, Anitha Ponnuswami, Spenser Chen, Tessa B Johung, Wenchao Sun & Michelle Monje

  3. Department of Neurosurgery, Stanford University, Stanford, California, USA

    Yujie Tang, Lining Liu, Pamelyn J Woo, Anitha Ponnuswami, Spenser Chen, Tessa B Johung & Michelle Monje

  4. Department of Pediatrics, Stanford University, Stanford, California, USA

    Yujie Tang, Lining Liu, Pamelyn J Woo, Anitha Ponnuswami, Spenser Chen, Tessa B Johung & Michelle Monje

  5. Department of Pathology, Stanford University, Stanford, California, USA

    Yujie Tang, Lining Liu, Pamelyn J Woo, Anitha Ponnuswami, Spenser Chen, Tessa B Johung & Michelle Monje

  6. CNRS, UMR 8203, Gustave Roussy, Université Paris-Sud, Villejuif, France

    Nathalene Truffaux, Marie-Anne Debily, Ludivine Le Dret & Jacques Grill

  7. Electrical and Computer Engineering, Texas Tech University, Lubbock, Texas, USA

    Noah E Berlow & Ranadip Pal

  8. Département de biologie, Université d'Evry-Val d'Essone, Evry, France

    Marie-Anne Debily

  9. Department of Pediatrics, Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, OHSU, Portland, Oregon, USA

    Lara E Davis, Elaine C Huang, Jinu Abraham & Charles Keller

  10. Laboratory of Molecular Neurooncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA

    Mari Kogiso, Yuchen Du, Lin Qi, Yulun Huang, Hua Mao & Xiao-Nan Li

  11. Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA

    Marianne Hütt-Cabezas & Eric H Raabe

  12. Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA

    Marianne Hütt-Cabezas & Eric H Raabe

  13. National Cancer Institute, Bethesda, Maryland, USA

    Katherine E Warren, Paul S Meltzer & Martha Quezado

  14. Department of Pediatric Oncology and Hematology, VU University Medical Center, Amsterdam, The Netherlands

    Dannis G van Vuurden & Esther Hulleman

  15. Neuro-Oncology Research Group Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands

    Dannis G van Vuurden & Esther Hulleman

  16. Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA

    Maryam Fouladi

  17. Children's Cancer Therapy Development Institute, Fort Collins, Colorado, USA

    Matthew N Svalina & Charles Keller

  18. Department of Pediatric Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada

    Cynthia Hawkins

  19. Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Cynthia Hawkins

  20. Center for Research Institute, Children's National Health Systems, Washington, DC, USA

    Javad Nazarian

  21. Department of Oncology, University Hospital of Navarra, Pamplona, Spain

    Marta M Alonso

  22. Departement de Cancerologie de l'Enfant et de l'Adolescent, Institut Gustave Roussy, Université Paris-Sud, Villejuif, France

    Jacques Grill

Authors
  1. Catherine S Grasso
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  2. Yujie Tang
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  33. Eric H Raabe
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  34. Esther Hulleman
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  35. Paul T Spellman
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  36. Xiao-Nan Li
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  37. Charles Keller
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  38. Ranadip Pal
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  40. Michelle Monje
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Contributions

C.K., M.M., J.G., Y.T., M.F., K.E.W., D.G.v.V., R.P., C.S.G., C.H., X.-N.L. and P.T.S. participated in the design or interpretation of the reported experiments or results. J.A., E.H., L.L., Y.T., A.P., S.C., P.J.W., T.B.J., M.H.-C., L.L.D., N.T., M.M., K.E.W., R.P., N.E.B., L.E.D., E.H.R. C.K., M.K., Y.D., L.Q., Y.H., C.S.G., M.Q., M.-A.D., J.N., M.M.A., W.S., E.C.H., M.J.Q., P.S.M., H.M., M.N.S., N.W. and X.-N.L. participated in the acquisition or analysis of data. M.M., C.S.G., C.K., J.G., Y.T., M.-A.D., L.L., R.P., N.T., E.H.R., D.G.v.V., N.E.B. and X.-N.L. participated in drafting or revising the manuscript. M.M., C.K., R.P. and J.G. supervised all aspects of the research.

Corresponding authors

Correspondence to Charles Keller or Michelle Monje.

Ethics declarations

Competing interests

N.E.B., C.K., L.E.D. and R.P. have filed an invention disclosure with Texas Tech University for probabilistic Boolean modeling of predicted drug combinations and are in the process of commercializing this approach. A US patent application has also been filed.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–10 and Supplementary Tables 1 and 5 (PDF 5837 kb)

Supplementary Table 2

STR fingerprints of the DIPG cell lines (XLSX 9 kb)

Supplementary Table 3

Sequencing statistics and identified mutations (XLSX 40 kb)

Supplementary Table 4

Calculated combination indices (XLSX 20 kb)

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Grasso, C., Tang, Y., Truffaux, N. et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 21, 555–559 (2015). https://doi.org/10.1038/nm.3855

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