Abstract | BACKGROUND: METHODS: A collaborative pre-clinical study was conducted using both a genetic BSG mouse model driven by PDGF-B signaling, p53 loss, and ectopic H3.3-K27M or H3.3-WT expression and an H3.3-K27M orthotopic DIPG xenograft model to confirm and extend previously published findings regarding the efficacy of panobinostat in vitro and in vivo. RESULTS: In vitro, panobinostat potently inhibited cell proliferation, viability, and clonogenicity and induced apoptosis of human and murine DIPG cells. In vivo analyses of tissue after short-term systemic administration of panobinostat to genetically engineered tumor-bearing mice indicated that the drug reached brainstem tumor tissue to a greater extent than normal brain tissue, reduced proliferation of tumor cells and increased levels of H3 acetylation, demonstrating target inhibition. Extended consecutive daily treatment of both genetic and orthotopic xenograft models with 10 or 20 mg/kg panobinostat consistently led to significant toxicity. Reduced, well-tolerated doses of panobinostat, however, did not prolong overall survival compared to vehicle-treated mice. CONCLUSION: Our collaborative pre-clinical study confirms that panobinostat is an effective targeted agent against DIPG human and murine tumor cells in vitro and in short-term in vivo efficacy studies in mice but does not significantly impact survival of mice bearing H3.3-K27M-mutant tumors. We suggest this may be due to toxicity associated with systemic administration of panobinostat that necessitated dose de-escalation.
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Authors | Tammy Hennika, Guo Hu, Nagore G Olaciregui, Kelly L Barton, Anahid Ehteda, Arjanna Chitranjan, Cecilia Chang, Andrew J Gifford, Maria Tsoli, David S Ziegler, Angel M Carcaboso, Oren J Becher |
Journal | PloS one
(PLoS One)
Vol. 12
Issue 1
Pg. e0169485
( 2017)
ISSN: 1932-6203 [Electronic] United States |
PMID | 28052119
(Publication Type: Journal Article)
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Chemical References |
- Histones
- Hydroxamic Acids
- Indoles
- Panobinostat
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Topics |
- Acetylation
(drug effects)
- Animals
- Apoptosis
(drug effects)
- Brain Stem Neoplasms
(drug therapy, pathology)
- Cell Line, Tumor
- Cell Proliferation
(drug effects)
- Cell Survival
(drug effects)
- Cerebral Cortex
(drug effects, pathology)
- Clone Cells
- Genetic Engineering
- Glioma
(drug therapy, pathology)
- Histones
(metabolism)
- Humans
- Hydroxamic Acids
(pharmacokinetics, pharmacology, therapeutic use)
- Indoles
(pharmacokinetics, pharmacology, therapeutic use)
- Inhibitory Concentration 50
- Mice, Inbred C57BL
- Panobinostat
- Treatment Outcome
- Xenograft Model Antitumor Assays
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