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

Mol Cancer Ther 2019 02 12;18(2):421-436. Epub 2018 Nov 12.

Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

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 and 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 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% ( < 0.001). Treatment with either BETis or BRD4 siRNA decreased Notch3 expression both and BRD4 inhibition also decreased the expression of targets, including Chromatin immunoprecipitation revealed that BRD4 was present at the 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.

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Source
http://mct.aacrjournals.org/lookup/doi/10.1158/1535-7163.MCT
Publisher Site
http://dx.doi.org/10.1158/1535-7163.MCT-18-0365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6363833PMC
February 2019
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