Cancers, Vol. 14, Pages 4256: An FDA-Approved Antifungal, Ketoconazole, and Its Novel Derivative Suppress tGLI1-Mediated Breast Cancer Brain Metastasis by Inhibiting the DNA-Binding Activity of Brain Metastasis-Promoting Transcription Factor tGLI1

Cancers, Vol. 14, Pages 4256: An FDA-Approved Antifungal, Ketoconazole, and Its Novel Derivative Suppress tGLI1-Mediated Breast Cancer Brain Metastasis by Inhibiting the DNA-Binding Activity of Brain Metastasis-Promoting Transcription Factor tGLI1 Cancers doi: 10.3390/cancers14174256 Authors: Daniel Doheny Sara Manore Sherona R. Sirkisoon Dongqin Zhu Noah R. Aguayo Alexandria Harrison Mariana Najjar Marlyn Anguelov Anderson O’Brien Cox Cristina M. Furdui Kounosuke Watabe Thomas Hollis Alexandra Thomas Roy Strowd Hui-Wen Lo The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ’s effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer an...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research