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Mol Cancer Ther. 2019 Feb;18(2):421-436. doi: 10.1158/1535-7163.MCT-18-0365. Epub 2018 Nov 12.

Predicting Novel Therapies and Targets: Regulation of Notch3 by the Bromodomain Protein BRD4.

Author information

1
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, Puerto Rico.
3
School of Biomedical Sciences, University of Queensland, Queensland, Australia.
4
John P. and Kathrine G. McGovern Medical School, The University of Texas, Houston, Texas.
5
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas.
7
Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
8
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
9
National Center for Advancing Translational Sciences, NIH, Rockville, Maryland.
10
ConverGene, Gaithersburg, Maryland.
11
Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. asood@mdanderson.org jroszik@mdanderson.org.
12
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
13
Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas. asood@mdanderson.org jroszik@mdanderson.org.
#
Contributed equally

Abstract

Systematic approaches for accurate repurposing of targeted therapies are needed. We developed and aimed to biologically validate our therapy predicting tool (TPT) for the repurposing of targeted therapies for specific tumor types by testing the role of Bromodomain and Extra-Terminal motif inhibitors (BETi) in inhibiting BRD4 function and downregulating Notch3 signaling in ovarian cancer.Utilizing established ovarian cancer preclinical models, we carried out in vitro and in vivo studies with clinically relevant BETis to determine their therapeutic effect and impact on Notch3 signaling.Treatment with BETis or siRNA-mediated BRD4 knockdown resulted in decreased cell viability, reduced cell proliferation, and increased cell apoptosis in vitro. In vivo studies with orthotopic mouse models demonstrated that treatment with BETi decreased tumor growth. In addition, knockdown of BRD4 with doxycycline-inducible shRNA increased survival up to 50% (P < 0.001). Treatment with either BETis or BRD4 siRNA decreased Notch3 expression both in vitro and in vivo BRD4 inhibition also decreased the expression of NOTCH3 targets, including HES1 Chromatin immunoprecipitation revealed that BRD4 was present at the NOTCH3 promoter.Our findings provide biological validation for the TPT by demonstrating that BETis can be an effective therapeutic agent for ovarian cancer by downregulating Notch3 expression.The TPT could rapidly identify candidate drugs for ovarian or other cancers along with novel companion biomarkers.

PMID:
30420565
PMCID:
PMC6363833
[Available on 2020-02-01]
DOI:
10.1158/1535-7163.MCT-18-0365

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