Abstract A133: Development of murine models to evaluate the impact of glucocorticoid receptor (GR) inhibition on chemotherapy response

Abstract

Abstract The glucocorticoid receptor (GR) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. GR is activated by its endogenous steroid hormone ligand, cortisol, and by synthetic glucocorticoid drugs such as dexamethasone. Several preclinical studies have established a role for GR in mediating resistance to both targeted therapies and conventional chemotherapies in epithelial cancers. Glucocorticoids have been reported to confer resistance to antimetabolites, taxanes, and platinum compounds in lung, prostate, bladder, renal, ovarian, and triple-negative breast cancers (Gassler et al., 2005; Li et al., 2017; Zhang et al., 2007). GR has also been reported to confer resistance to antiandrogen therapies in prostate cancer (Arora et al., 2013). Therefore, a molecule that inhibits GR activation could attenuate the development of resistance to cancer therapeutics. We are developing novel GR inhibitors that effectively block GR transcriptional activity in cells by competing for ligand binding and blocking GR-Coactivator interactions. In vitro, GR inhibition enhances the efficacy of chemotherapeutic agents under conditions supporting GR activation. In humans, the predominant glucocorticoid is cortisol, while in mice the predominant glucocorticoid is corticosterone (Siswanto et al., 2008). Corticosterone is a potent agonist of murine GR, but a weak agonist of human GR. When human tumor cells are grown in mice, GR is not active in the tumor cells due to the lack of circulating cortisol. Therefore it is necessary to provide exogenous cortisol to fully activate GR. Using xenograft models of ovarian and triple-negative breast cancer, we find that tumors grown in mice with physiologically relevant circulating cortisol levels are significantly less sensitive to standard-of-care chemotherapy than those grown in the absence of cortisol. Inhibition of GR is effective at restoring the response to chemotherapy in these models. These results demonstrate the therapeutic potential of GR inhibitors in combination with clinically utilized chemotherapeutics. Furthermore, the in vivo models developed provide a milieu for testing and developing GR inhibitors. Citation Format: Nadine Jahchan, Haiying Zhou, James Stice, Wayne Kong, Dan McWeeney, Daqing Sun, Yosup Rew, Xiaohui Du, Liusheng Zhu, Qiuping Ye, Erica L. Jackson, Valeria Fantin. Development of murine models to evaluate the impact of glucocorticoid receptor (GR) inhibition on chemotherapy response [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A133.