Abstract 680: Identification of GLI1 antagonists for breast cancer therapy

Introduction: The transcription factor, glioma-associated oncogene homolog 1 (GLI1) is a downstream marker for hedgehog (Hh) pathway activation. Recently, Hh-GLI has emerged as a central pathway target in several human cancers (breast, leukemia, lung etc.) with elevated GLI1 in breast cancer having been linked to poor survival outcomes. A number of GLI targeted inhibitors have been shown to inhibit Hh/GLI signaling with some having efficacy in tumor models. We have previously demonstrated that siRNA downregulation of GLI1 expression in inflammatory breast cancer reduced proliferation and migration[1]. Further, we previously demonstrated the feasibility of employing a high throughput (HT) approach to profile drugs in dose response in cell line panels [2]. In this study, we have taken a comprehensive approach to profile a panel of GLI antagonists (including GANTS, HPIs, ATO and JK184) in a range of breast cancer cell lines with varying GLI1 expression levels to identify those with effects on growth. Experiment procedure: to assess cell proliferation, we employed an automated quantitative high throughput (qHT) approach to profile compounds on three phenotypic subtypes of breast cancer cell line models: triple negative breast cancer (TNBC), inflammatory breast cancer, and Claudin low breast cancer cell lines. High-content imaging of nuclear count utilizing Hoechst staining was also used as an alternative measure of proliferation. Quantitative PCR and Western blotting was used to assess the effects of the inhibitors on the GLI1 expression. Results: A subset of GLI antagonists were identified as decreasing cell growth and viability in all the cell lines. Conclusion: Several agents showed efficacy in in vitro BC cancer models demonstrating that GLI inhibitors may be a valid therapeutic approach for targeting GLI-dependent BC cancers. [1] Z. Thomas, W. Gibson, J. Sexton, K. Aird, S. Ingram, A. Aldrich, H. Lyerly, G. Devi, K. Williams, Targeting GLI1 expression in human inflammatory breast cancer cells enhances apoptosis and attenuates migration. British Journal of Cancer 104 (2011) 1575-1586. [2] K.P. Williams, J.L. Allensworth, S.M. Ingram, G.R. Smith, A.J. Aldrich, J. Z Sexton, G. R Devi, Quantitative high-throughput efficacy profiling of approved oncology drugs in inflammatory breast cancer models of acquired drug resistance and re-sensitization. Cancer Lett. 337 (2013) 77-89. Funded in part by DOD/CDMRP IDEA W81XWH-13-1-0141 award (KPW); NIH U54CA156735 (KPW);