Functionally defined therapeutic targets in diffuse intrinsic pontine glioma

Catherine S. Grasso; Yujie Tang; Nathalene Truffaux; Noah E. Berlow; Lining Liu; Marie Anne Debily; Michael J. Quist; Lara E. Davis; Elaine C. Huang; Pamelyn J. Woo; Anitha Ponnuswami; Spenser Chen; Tessa B. Johung; Wenchao Sun; Mari Kogiso; Yuchen Du; Lin Qi; Yulun Huang; Marianne Hütt-Cabezas; Katherine E. Warren; Ludivine Le Dret; Paul S. Meltzer; Hua Mao; Martha Quezado; Dannis G. Van Vuurden; Jinu Abraham; Maryam Fouladi; Matthew N. Svalina; Nicholas Wang; Cynthia Hawkins; Javad Nazarian; Marta M. Alonso; Eric H. Raabe; Esther Hulleman; Paul T. Spellman; Xiao Nan Li; Charles Keller; Ranadip Pal; Jacques Grill; Michelle Monje

doi:10.1038/nm.3855

Functionally defined therapeutic targets in diffuse intrinsic pontine glioma

Catherine S. Grasso, Yujie Tang, Nathalene Truffaux, Noah E. Berlow, Lining Liu, Marie Anne Debily, Michael J. Quist, Lara E. Davis, Elaine C. Huang, Pamelyn J. Woo, Anitha Ponnuswami, Spenser Chen, Tessa B. Johung, Wenchao Sun, Mari Kogiso, Yuchen Du, Lin Qi, Yulun Huang, Marianne Hütt-Cabezas, Katherine E. WarrenLudivine Le Dret, Paul S. Meltzer, Hua Mao, Martha Quezado, Dannis G. Van Vuurden, Jinu Abraham, Maryam Fouladi, Matthew N. Svalina, Nicholas Wang, Cynthia Hawkins, Javad Nazarian, Marta M. Alonso, Eric H. Raabe, Esther Hulleman, Paul T. Spellman, Xiao Nan Li, Charles Keller^*, Ranadip Pal, Jacques Grill, Michelle Monje

^*Corresponding author for this work

Pediatrics

Research output: Contribution to journal › Article › peer-review

443 Scopus citations

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.

Original language	English (US)
Pages (from-to)	555-559
Number of pages	5
Journal	Nature Medicine
Volume	21
Issue number	6
DOIs	https://doi.org/10.1038/nm.3855
State	Published - Jun 9 2015

Funding

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.).

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Grasso, C. S., Tang, Y., Truffaux, N., Berlow, N. E., Liu, L., Debily, M. A., Quist, M. J., Davis, L. E., Huang, E. C., Woo, P. J., Ponnuswami, A., Chen, S., Johung, T. B., Sun, W., Kogiso, M., Du, Y., Qi, L., Huang, Y., Hütt-Cabezas, M., ... Monje, M. (2015). Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nature Medicine, 21(6), 555-559. https://doi.org/10.1038/nm.3855

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title = "Functionally defined therapeutic targets in diffuse intrinsic pontine glioma",

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.",

author = "Grasso, {Catherine S.} and Yujie Tang and Nathalene Truffaux and Berlow, {Noah E.} and Lining Liu and Debily, {Marie Anne} and Quist, {Michael J.} and Davis, {Lara E.} and Huang, {Elaine C.} and Woo, {Pamelyn J.} and Anitha Ponnuswami and Spenser Chen and Johung, {Tessa B.} and Wenchao Sun and Mari Kogiso and Yuchen Du and Lin Qi and Yulun Huang and Marianne H{\"u}tt-Cabezas and Warren, {Katherine E.} and {Le Dret}, Ludivine and Meltzer, {Paul S.} and Hua Mao and Martha Quezado and {Van Vuurden}, {Dannis G.} and Jinu Abraham and Maryam Fouladi and Svalina, {Matthew N.} and Nicholas Wang and Cynthia Hawkins and Javad Nazarian and Alonso, {Marta M.} and Raabe, {Eric H.} and Esther Hulleman and Spellman, {Paul T.} and Li, {Xiao Nan} and Charles Keller and Ranadip Pal and Jacques Grill and Michelle Monje",

year = "2015",

month = jun,

day = "9",

doi = "10.1038/nm.3855",

language = "English (US)",

volume = "21",

pages = "555--559",

journal = "Nature Medicine",

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Grasso, CS, Tang, Y, Truffaux, N, Berlow, NE, Liu, L, Debily, MA, Quist, MJ, Davis, LE, Huang, EC, Woo, PJ, Ponnuswami, A, Chen, S, Johung, TB, Sun, W, Kogiso, M, Du, Y, Qi, L, Huang, Y, Hütt-Cabezas, M, Warren, KE, Le Dret, L, Meltzer, PS, Mao, H, Quezado, M, Van Vuurden, DG, Abraham, J, Fouladi, M, Svalina, MN, Wang, N, Hawkins, C, Nazarian, J, Alonso, MM, Raabe, EH, Hulleman, E, Spellman, PT, Li, XN, Keller, C, Pal, R, Grill, J & Monje, M 2015, 'Functionally defined therapeutic targets in diffuse intrinsic pontine glioma', Nature Medicine, vol. 21, no. 6, pp. 555-559. https://doi.org/10.1038/nm.3855

TY - JOUR

T1 - Functionally defined therapeutic targets in diffuse intrinsic pontine glioma

AU - Grasso, Catherine S.

AU - Tang, Yujie

AU - Truffaux, Nathalene

AU - Berlow, Noah E.

AU - Liu, Lining

AU - Debily, Marie Anne

AU - Quist, Michael J.

AU - Davis, Lara E.

AU - Huang, Elaine C.

AU - Woo, Pamelyn J.

AU - Ponnuswami, Anitha

AU - Chen, Spenser

AU - Johung, Tessa B.

AU - Sun, Wenchao

AU - Kogiso, Mari

AU - Du, Yuchen

AU - Qi, Lin

AU - Huang, Yulun

AU - Hütt-Cabezas, Marianne

AU - Warren, Katherine E.

AU - Le Dret, Ludivine

AU - Meltzer, Paul S.

AU - Mao, Hua

AU - Quezado, Martha

AU - Van Vuurden, Dannis G.

AU - Abraham, Jinu

AU - Fouladi, Maryam

AU - Svalina, Matthew N.

AU - Wang, Nicholas

AU - Hawkins, Cynthia

AU - Nazarian, Javad

AU - Alonso, Marta M.

AU - Raabe, Eric H.

AU - Hulleman, Esther

AU - Spellman, Paul T.

AU - Li, Xiao Nan

AU - Keller, Charles

AU - Pal, Ranadip

AU - Grill, Jacques

AU - Monje, Michelle

PY - 2015/6/9

Y1 - 2015/6/9

N2 - 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.

AB - 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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DO - 10.1038/nm.3855

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C2 - 25939062

AN - SCOPUS:84930764914

SN - 1078-8956

VL - 21

SP - 555

EP - 559

JO - Nature Medicine

JF - Nature Medicine

IS - 6

ER -

Functionally defined therapeutic targets in diffuse intrinsic pontine glioma

Abstract

Funding

ASJC Scopus subject areas

UN SDGs

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