Figure 1 from ORIC-101, a Glucocorticoid Receptor Antagonist, in Combination with Nab-Paclitaxel in Patients with Advanced Solid Tumors
Authors: Chen Christopher T. , Khanna Vishesh , Kummar Shivaani , Abdul-Karim Raghad M. , Sommerhalder David , Tolcher Anthony W. , Ueno Naoto T. , Davis Sarah Lindsey , Orr Douglas W. , Hamilton Erika , Patel Manish R. , Spira Alexander I. , Jauhari Shekeab , Florou Vaia , Duff Maureen , Xu Rongda , Wang Jian , Barkund Shravani R. , Zhou Haiying , Pankov Aleksandr , Kong Wayne , Jahchan Nadine S. , Jackson Erica L. , Sun Jessica D. , Junttila Melissa R. , Multani Pratik S. , Daemen Anneleen , Chow Maneval Edna , Munster Pamela N. 
Published: September 2024

<p>GR antagonism by ORIC-101 overcomes taxane resistance in preclinical models. <b>A</b> and <b>B,</b> Effect of ORIC-101 on dexamethasone-induced chemoprotection <i>in vitro</i> as measured by (<b>A</b>) caspase 3/7 apoptosis assays and (<b>B</b>) colony formation assays, in three TNBC lines (HCC1806, MDA-MB-231, Hs578T), three PDAC lines (BxPC3, SW1990, PSN1), and ovarian cancer line COV362. Veh: vehicle; Dex: 30 nmol/L dexamethasone; 101: 0.5 μmol/L ORIC-101; Chemo = 100 nmol/L paclitaxel + 100 nmol/L gemcitabine; PTX = 100 nmol/L paclitaxel; DTX = 100 nmol/L docetaxel; Gem = 100 nmol/L gemcitabine. <b>A,</b> The caspase activities of Veh were assigned as 1, and the values for other conditions were relative to Veh. One representative experiment with three biological repeats is shown (mean ± SEM). *, <i>P</i> < 0.05; **, <i>P</i> < 0.01; ***, <i>P</i> < 0.001 by one-way ANOVA using Tukey’s test to correct for multiple comparisons. <b>B,</b> One representative experiment with three biological repeats is shown. Numbers in white indicate the percentage of confluency quantitated by Celigo S. <b>C,</b> Effect of ORIC-101 on paclitaxel response in taxane-naïve HCC1806 TNBC xenografts in cortisol-treated mice. Mice were treated with paclitaxel 20 mg/kg by intraperitoneal injection every 3 days for a total of eight cycles (20 mg/kg, IP, Q3D × 8), cortisol (100 mg/L in drinking water, <i>ad libitum</i>) or ORIC-101 75 mg/kg by oral administration twice daily (75 mg/kg, PO, BID) starting on day 0 for the duration of the study. Arrowheads indicate PTX dosing days. Data are displayed as mean ± SEM. <b>D</b> and <b>E,</b> Effect of ORIC-101 in paclitaxel-relapsed HCC1806 TNBC xenografts in cortisol-treated mice. <b>D,</b> Animals were dosed with paclitaxel (15 mg/kg, IP, Q3Dx5) as indicated by the black arrowheads or ORIC-101 (150 mg/kg, PO, QD) as indicated by gray line. <i>n</i> = 15 in each group. Data is displayed as mean ± SEM. <b>E,</b> PFS, defined as the time elapsed between treatment initiation of the second cycle of paclitaxel and tumor progression or death from any cause, as a percentage of all animals in each cohort. A Kaplan–Meier plot was constructed to show the percentage of animals remaining in the study following treatment (<i>P</i> < 0.0001 by log-rank test). <b>F,</b> Overall survival, defined as the time elapsed between treatment initiation of the second cycle of paclitaxel and death from any cause as a percentage of all animals in each cohort, was not significantly different between the cohorts (by log-rank test).</p>