Functionally defined therapeutic targets in diffuse intrinsic pontine glioma
Open accessAbstract
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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An array of novel compounds targeting the enzymatic domains of methyltransferases, demethylases or chromatin methylation reader proteins have entered the preclinical and clinical arena in recent years.
“An array of novel compounds targeting the enzymatic domains of methyltransferases that 'write' chromatin methylation, demethylases that 'erase' this modification or chromatin proteins that have specialised domains that 'read', or bind, chromatin methylation have entered the preclinical and clinical arena in recent years 120 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [120]
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- Authors
- 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., Warren, K. E., Le Dret, L., Meltzer, P. S., Mao, H., Quezado, M., van Vuurden, D. G., Abraham, J., Fouladi, M., Svalina, M. N., Wang, N., Hawkins, C., Nazarian, J., Alonso, M. M., Raabe, E. H., Hulleman, E., Spellman, P. T., Li, X.-N., Keller, C., Pal, R., Grill, J., & Monje, M.
- Affiliations
- Oregon Health & Science University (US)
- Shanghai Jiao Tong University (CN)
- Texas Tech University (US)
- Stanford Medicine (US)
- Université Paris-Sud (FR)
- Stanford University (US)
- Baylor College of Medicine (US)
- Johns Hopkins University (US)
- National Institutes of Health (US)
- Cincinnati Children's Hospital Medical Center (US)
- University of Toronto (CA)
- Children's National (US)
- Universidad de Navarra (ES)
- Cancer Center Amsterdam (NL)
- Corresponding author
- Keller, Charles
- Monje, Michelle
- ORCID
- Grasso, Catherine S
- Tang, Yujie
- Berlow, Noah E
- Liu, Lining
- Debily, Marie-Anne
- Davis, Lara E
- Huang, Elaine C
- Woo, Pamelyn J
- Ponnuswami, Anitha
- Chen, Spenser
- Sun, Wenchao
- Qi, Lin
- Huang, Yulun
- Warren, Katherine E
- Meltzer, Paul S
- Mao, Hua
- Quezado, Martha
- Abraham, Jinu
- Fouladi, Maryam
- Svalina, Matthew N
- Wang, Nicholas
- Hawkins, Cynthia
- Nazarian, Javad
- Alonso, Marta M
- Raabe, Eric H
- Hulleman, Esther
- Spellman, Paul T
- Li, Xiao-Nan
- Keller, Charles
- Pal, Ranadip
- Grill, Jacques
- Monje, Michelle
- Venue
- Nature Medicine
- Published
- 2015-05-04
- Volume
- 21
- Issue
- 6
- Pages
- 555-559
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4862411
- OpenAlex
- W2051921450
- Cited by
- 687
- References
- 25
- Citations by year
- 2026: 38 · 2025: 33 · 2024: 73 · 2023: 69 · 2022: 60 · 2021: 65 · 2020: 84 · 2019: 64 · 2018: 62 · 2017: 80 · 2016: 39 · 2015: 18 · 2014: 1
- FWCI
- 36.87
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-07-07)
- Open access
- green
- pure.amsterdamumc.nl
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- National Science Foundation (0953366)
- U.S. Department of Defense
- Alex's Lemonade Stand Foundation for Childhood Cancer
- CureSearch for Children's Cancer
- Virginia and D.K. Ludwig Fund for Cancer Research
- Oregon Health and Science University
- Northwestern University
- Johns Hopkins University
- Cure Starts Now Foundation
- Reflections of Grace Foundation
- University of Warwick
- National Institutes of Health
- National Cancer Institute (P30CA006973)
- National Institute of Neurological Disorders and Stroke (K08NS070926)
- Topics
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- diffuse intrinsic pontine glioma, therapeutic target, panobinostat, histone deacetylase inhibitors, GSK-J4, histone demethylase inhibitors, combination therapy, drug synergy, orthotopic xenograft, pediatric brain tumors, chemical screen
- MeSH terms
- Panobinostat, Animals, Benzazepines, Disease Models, Animal, Drug Synergism, Glioma, Humans, Hydroxamic Acids, Indoles, Pyrimidines, Sequence Analysis, RNA, Brain Stem Neoplasms, Xenograft Model Antitumor Assays
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