On December 16, 2019 ORIC Pharmaceuticals, a privately held, clinical stage oncology company focused on developing treatments that address mechanisms of therapeutic resistance, reported that new preclinical data on its lead program, ORIC-101, a selective and potent glucocorticoid receptor (GR) antagonist currently being investigated in a Phase 1b clinical trial in combination with nab-paclitaxel in patients with advanced solid tumors, at the 2019 San Antonio Breast Cancer Symposium (Press release, ORIC Pharmaceuticals, DEC 16, 2019, https://www.prnewswire.com/news-releases/oric-pharmaceuticals-presents-preclinical-data-on-glucocorticoid-receptor-antagonist-at-2019-san-antonio-breast-cancer-symposium-300974917.html [SID1234552411]).
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The ORIC-101 preclinical data were presented in a poster titled, "ORIC-101 Robustly Inhibits the Glucocorticoid Pathway and Overcomes Chemoresistance in TNBC" (Program Number: P6-03-24, Abstract #2507).
GR is highly expressed in a variety of cancers including prostate, pancreatic, ovarian, triple-negative breast cancer (TNBC) and endometrial cancers. Preclinical studies have indicated that activation of GR reduces the efficacy of chemotherapy, while inhibition of GR with the antagonist ORIC-101 enhances the efficacy of chemotherapy in multiple solid tumor models.
ORIC-101 potently sensitizes TNBC cells to chemotherapy by reversing GR-mediated resistance through the epithelial-to-mesenchymal transition and anti-apoptosis pathways, in both in vitro and in vivo preclinical models. The poster presented a GR activation signature developed at ORIC that includes the direct GR transcriptional targets FKBP5 and GILZ and subsequently validated both genes as ORIC-101 pharmacodynamic (PD) biomarkers. The relationship between PD biomarkers, pharmacokinetics and efficacy in preclinical models was also assessed. The data demonstrated that ORIC-101 robustly inhibits the transcriptional induction of PD biomarkers and fully reverses GR-mediated chemoresistance in vitro and in vivo.
In addition to its ongoing Phase 1b clinical trial of ORIC-101 in combination with nab-paclitaxel, ORIC is also conducting a second Phase 1b clinical trial of ORIC-101 in combination with enzalutamide in patients with metastatic prostate cancer.