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Nat Med. 2015 Jun;21(6):555-9. doi: 10.1038/nm.3855. Epub 2015 May 4.

Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.

Author information

1
Center for Spatial Systems Biomedicine, Department of Molecular and Medical Genetics, Oregon Health &Science University (OHSU), Portland, Oregon, USA.
2
1] Department of Neurology, Stanford University, Stanford, California, USA. [2] Department of Neurosurgery, Stanford University, Stanford, California, USA. [3] Department of Pediatrics, Stanford University, Stanford, California, USA. [4] Department of Pathology, Stanford University, Stanford, California, USA. [5] 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 Suzhou University, Suzhou, China (Y.H.).
3
CNRS, UMR 8203, Gustave Roussy, Université Paris-Sud, Villejuif, France.
4
Electrical and Computer Engineering, Texas Tech University, Lubbock, Texas, USA.
5
1] Department of Neurology, Stanford University, Stanford, California, USA. [2] Department of Neurosurgery, Stanford University, Stanford, California, USA. [3] Department of Pediatrics, Stanford University, Stanford, California, USA. [4] Department of Pathology, Stanford University, Stanford, California, USA.
6
1] CNRS, UMR 8203, Gustave Roussy, Université Paris-Sud, Villejuif, France. [2] Département de biologie, Université d'Evry-Val d'Essone, Evry, France.
7
Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, OHSU, Portland, Oregon, USA.
8
Department of Neurology, Stanford University, Stanford, California, USA.
9
Laboratory of Molecular Neurooncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
10
1] Laboratory of Molecular Neurooncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA. [2] 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 Suzhou University, Suzhou, China (Y.H.).
11
1] Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
12
National Cancer Institute, Bethesda, Maryland, USA.
13
1] Department of Pediatric Oncology and Hematology, VU University Medical Center, Amsterdam, The Netherlands. [2] Neuro-Oncology Research Group Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
14
Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
15
1] Center for Spatial Systems Biomedicine, Department of Molecular and Medical Genetics, Oregon Health &Science University (OHSU), Portland, Oregon, USA. [2] Children's Cancer Therapy Development Institute, Fort Collins, Colorado, USA.
16
1] Department of Pediatric Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada. [2] Labatt Brain Tumor Research Centre, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
17
Center for Research Institute, Children's National Health Systems, Washington, DC, USA.
18
Department of Oncology, University Hospital of Navarra, Pamplona, Spain.
19
1] Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, OHSU, Portland, Oregon, USA. [2] Children's Cancer Therapy Development Institute, Fort Collins, Colorado, USA.
20
1] CNRS, UMR 8203, Gustave Roussy, Université Paris-Sud, Villejuif, France. [2] Departement de Cancerologie de l'Enfant et de l'Adolescent, Institut Gustave Roussy, Université Paris-Sud, Villejuif, France.

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.

PMID:
25939062
PMCID:
PMC4862411
DOI:
10.1038/nm.3855
[Indexed for MEDLINE]
Free PMC Article

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