Abstract P6-03-24: ORIC-101 robustly inhibits the glucocorticoid pathway and overcomes chemoresistance in triple-negative breast cancer

Abstract

Abstract ORIC-101 is a novel and selective glucocorticoid receptor (GR) antagonist currently in Ph1 clinical evaluation in solid tumors. In preclinical models, ORIC-101 potently sensitized triple-negative breast cancer (TNBC) cells to chemotherapy by inhibiting GR-mediated resistance through the epithelial-to-mesenchymal transition and anti-apoptosis pathways, both in vitro and in vivo. To inform the clinical development of ORIC-101, we identified pharmacodynamic (PD) biomarkers and established a relationship between those biomarkers, pharmacokinetics (PK), and efficacy in preclinical models. Using genome-wide profiling, we developed a GR activation signature that includes the direct GR transcriptional targets FKBP5 and GILZ, and subsequently validated both genes as ORIC-101 PD biomarkers in a panel of cell lines. We demonstrated that FKBP5 and GILZ are transcriptionally induced by glucocorticoids in a dose-dependent manner, and that the degree of their transcriptional activation is correlated with basal levels of GR in these models. We showed that ORIC-101 robustly inhibits the transcriptional induction of FKBP5 and GILZ and fully reverses GR-mediated chemoresistance in vitro and in vivo. Furthermore, FKBP5 and GILZ are reliable PD biomarkers for ORIC-101 in human-derived peripheral blood mononuclear cells (PBMCs). Importantly, by integrating PK, PD, and efficacy results from numerous preclinical studies, we captured the relationship between ORIC-101 PK, PD biomarker modulation, and chemopotentiation. Altogether, FKBP5 and GILZ mRNA levels are robust PD biomarkers to measure GR pathway engagement and modulation which corresponds with efficacy in response to GR antagonist treatment in preclinical models. These findings will guide the clinical development of ORIC-101 in TNBC. Citation Format: Haiying Zhou, Qiuping Ye, Aleksandr Pankov, Wayne Kong, Shravani Barkund, Lori S. Friedman, Jessica D. Sun, Omar Kabbarah. ORIC-101 robustly inhibits the glucocorticoid pathway and overcomes chemoresistance in triple-negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-03-24.