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| Status |
Public on Feb 12, 2021 |
| Title |
Combination of CBL0137 and Panobinostat in DIPG |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Diffuse intrinsic pontine glioma (DIPG) is an aggressive and incurable childhood brain tumor for which new treatments are needed. A high throughput drug screen of 3600 pharmaceutical compounds found that anti-malarials, including quinacrine had potent activity against DIPG neurospheres. CBL0137 is a novel anti-cancer compound developed from quinacrine, which targets Facilitates Chromatin Transcription (FACT), a chromatin remodelling complex involved in transcription, replication, and DNA repair. We have found that CBL0137 displays profound cytotoxic activity against a panel of patient derived DIPG cultures, inhibiting cell proliferation and clonogenic potential, restoring tumor suppressor TP53 and Rb activity and inducing cell death through induction of apoptosis. Moreover, in an orthotopic model of DIPG, treatment with CBL0137 significantly extended animal survival. Histone mutations leading to the loss of histone trimethylation result in epigenetic dysregulation driving DIPG tumorigenesis. Treatment with CBL0137 targets this epigenetic defect, restoring both histone H3.3 acetylation and trimethylation and leading to tumor cell death. Combined epigenetic treatment with the histone deacetylase (HDAC) inhibitor panobinostat led to inhibition of the Rb/E2F1 pathway, and increased the enzymatic activity of enhancer of zeste homolog 2 (EZH2), leading to the restoration of H3K27 trimethylation. This combination therapy had synergistic activity against DIPG neurospheres with induction of apoptosis. Consistent with the in vitro results, the combination of CBL0137 and panobinostat significantly prolonged the survival of mice bearing DIPG orthografts suggesting a potential treatment strategy for DIPG.
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| Overall design |
HSJD-DIPG007 cells were treated with DMSO, CBL0137 (0.6μM), panobinostat (20nM) and the combination of the two agents for 24 hours. After incubation, cells were harvested and washed 2x with PBS. RNA was then extracted using the RNeasy extraction kit (Qiagen) according to the manufacturer’s instruction. Gene expression data was obtained through the Affymetrix Clariom D Human microarray platform, containing 6,281,169 probes and 40,899 probesets. Probesets were processed using the Robust MultiArray (RMA) pipeline (PMID 21070630) followed by probeset annotation to gene symbols using the Bioconductor AnnotationDbi pipeline (PMID 16939789).
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| Contributor(s) |
Ehteda A, Simon S, Franshaw L, Giorgi FM, Liu J, Hayden E, Joshi S, Pang CN, Pandher R, Mayoh C, Khan A, Ung C, Tolhurst O, Kankean A, Gopalakrishnan A, Trebilcock P, Gurova K, Gudkov A, Norris MD, Haber M, Vittorio O, Tsoli M, Ziegler DS |
| Citation(s) |
33852836 |
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| Submission date |
Jun 29, 2020 |
| Last update date |
Oct 11, 2021 |
| Contact name |
Chi Nam Ignatius Pang |
| E-mail(s) |
[email protected]
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| Organization name |
The University of New South Wales
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| Department |
The NSW Systems Biology Initiative
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| Lab |
Wilkins Lab
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| Street address |
School of Biotechnology and Biomolecular Sciences, UNSW Australia
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| City |
Sydney |
| State/province |
NSW |
| ZIP/Postal code |
2052 |
| Country |
Australia |
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| Platforms (1) |
| GPL28782 |
[Clariom_D_Human] Affymetrix Human Clariom D Assay [CDF: ClariomDHuman_Hs_ENSG.cdf] |
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| Samples (12)
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| GSM4644323 |
CBL0137 treatment, biological replicate 1 |
| GSM4644324 |
CBL0137 treatment, biological replicate 2 |
| GSM4644325 |
CBL0137 treatment, biological replicate 3 |
| GSM4644326 |
Combined CBL0137 and Panobinostat treatment, biological replicate 1 |
| GSM4644327 |
Combined CBL0137 and Panobinostat treatment, biological replicate 2 |
| GSM4644328 |
Combined CBL0137 and Panobinostat treatment, biological replicate 3 |
| GSM4644329 |
Control (DMSO), biological replicate 1 |
| GSM4644330 |
Control (DMSO), biological replicate 2 |
| GSM4644331 |
Control (DMSO), biological replicate 3 |
| GSM4644332 |
Panobinostat treatment, biological replicate 1 |
| GSM4644333 |
Panobinostat treatment, biological replicate 2 |
| GSM4644334 |
Panobinostat treatment, biological replicate 3 |
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| Relations |
| BioProject |
PRJNA642726 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE153441_RAW.tar |
350.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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