Functionally defined therapeutic targets in diffuse intrinsic pontine glioma.
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.
Center for Spatial Systems Biomedicine, Department of Molecular and Medical Genetics, Oregon Health &Science University (OHSU), Portland, Oregon, USA.
Catherine S
CS
Grasso
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.).
Yujie
Y
Tang
CNRS, UMR 8203, Gustave Roussy, Université Paris-Sud, Villejuif, France.
Nathalene
N
Truffaux
Electrical and Computer Engineering, Texas Tech University, Lubbock, Texas, USA.
Noah E
NE
Berlow
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.
Lining
L
Liu
1] CNRS, UMR 8203, Gustave Roussy, Université Paris-Sud, Villejuif, France. [2] Département de biologie, Université d'Evry-Val d'Essone, Evry, France.
Marie-Anne
MA
Debily
Center for Spatial Systems Biomedicine, Department of Molecular and Medical Genetics, Oregon Health &Science University (OHSU), Portland, Oregon, USA.
Michael J
MJ
Quist
Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, OHSU, Portland, Oregon, USA.
Lara E
LE
Davis
Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, OHSU, Portland, Oregon, USA.
Elaine C
EC
Huang
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.
Pamelyn J
PJ
Woo
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.
Anitha
A
Ponnuswami
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.
Spenser
S
Chen
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.
Tessa B
TB
Johung
Department of Neurology, Stanford University, Stanford, California, USA.
Wenchao
0000000343062896
W
Sun
Laboratory of Molecular Neurooncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Mari
M
Kogiso
Laboratory of Molecular Neurooncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Yuchen
Y
Du
Laboratory of Molecular Neurooncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Lin
L
Qi
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.).
Yulun
Y
Huang
1] Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Marianne
M
Hütt-Cabezas
National Cancer Institute, Bethesda, Maryland, USA.
Katherine E
KE
Warren
CNRS, UMR 8203, Gustave Roussy, Université Paris-Sud, Villejuif, France.
Ludivine
L
Le Dret
National Cancer Institute, Bethesda, Maryland, USA.
Paul S
PS
Meltzer
Laboratory of Molecular Neurooncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Hua
H
Mao
National Cancer Institute, Bethesda, Maryland, USA.
Martha
M
Quezado
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.
Dannis G
DG
van Vuurden
Pediatric Cancer Biology Program, Papé Family Pediatric Research Institute, Department of Pediatrics, OHSU, Portland, Oregon, USA.
Jinu
J
Abraham
Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Maryam
M
Fouladi
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.
Matthew N
MN
Svalina
Center for Spatial Systems Biomedicine, Department of Molecular and Medical Genetics, Oregon Health &Science University (OHSU), Portland, Oregon, USA.
Nicholas
N
Wang
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.
Cynthia
C
Hawkins
Center for Research Institute, Children's National Health Systems, Washington, DC, USA.
Javad
J
Nazarian
Department of Oncology, University Hospital of Navarra, Pamplona, Spain.
Marta M
MM
Alonso
1] Department of Oncology, Johns Hopkins University, Baltimore, Maryland, USA. [2] Department of Pathology, Johns Hopkins University, Baltimore, Maryland, USA.
Eric H
EH
Raabe
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.
Esther
E
Hulleman
Center for Spatial Systems Biomedicine, Department of Molecular and Medical Genetics, Oregon Health &Science University (OHSU), Portland, Oregon, USA.
Paul T
PT
Spellman
Laboratory of Molecular Neurooncology, Texas Children's Cancer Center, Baylor College of Medicine, Houston, Texas, USA.
Xiao-Nan
XN
Li
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.
Charles
0000000325057487
C
Keller
Electrical and Computer Engineering, Texas Tech University, Lubbock, Texas, USA.
Ranadip
R
Pal
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.
Jacques
J
Grill
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.
Michelle
M
Monje
D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage*; D020295:Brain Stem Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004195:Disease Models, Animal; D004357:Drug Synergism; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D007211:Indoles / Q000008:administration & dosage*; D000077767:Panobinostat; D011743:Pyrimidines / Q000008:administration & dosage*; D017423:Sequence Analysis, RNA; D023041:Xenograft Model Antitumor Assays
D001552:Benzazepines; C000593030:GSK-J4; D006877:Hydroxamic Acids; D007211:Indoles; D011743:Pyrimidines; D000077767:Panobinostat