Abstract 3623: Preclinical efficacy of the selective GR antagonist, CORT125134

Abstract

Abstract The role of activation of the glucocorticoid receptor (GR) in the response of several solid tumor types to chemotherapy has been reported by several groups. Skor et al1 have demonstrated that the non-selective GR antagonist mifepristone can potentiate the effect of paclitaxel in a mouse xenograft derived from a human triple negative breast cancer (TNBC) cell line. GR activation is thought to play a role in the regulation of pro- and anti-apoptotic genes. Isikbay et al2 have demonstrated the benefits of combining androgen deprivation therapy with GR antagonism in prostate cancer xenograft model. Signaling via GR appears to be able to compensate for lack of androgen receptor signaling, and to contribute to castrate resistance. CORT125134 is a novel, selective GR antagonist being developed for the treatment of a variety of solid tumors, in combination with an appropriate standard of care agent. CORT125134 is currently being studied in a Phase1/2 study in solid tumors, in combination with nab-paclitaxel. The efficacy of CORT125134 in combination with standard of care agents has been investigated in mouse xenograft models of several tumor types. Previous reports of the benefit of adding a GR antagonist to chemotherapy in a TNBC model and an ovarian cancer model have been confirmed. An enhancement of the anti-tumor effect of castration by the addition of a GR antagonist has been confirmed in a model of prostate cancer. In addition, CORT125134 has been shown to provide a significant improvement in the efficacy of paclitaxel in a pancreatic cancer model. In a MIAPaca-2 xenograft model, paclitaxel was given i.v. every 4 days either alone or in combination with CORT125134. The combination provided significantly better tumor group inhibition than paclitaxel alone (p<0.0001). These encouraging results in a pancreatic cancer model extend the potential utility of GR antagonism in a variety of solid tumor types. In the TNBC model, alternative dosing regimens have been investigated, and suggest that stress during dosing is a confounding factor in these studies. 1. Skor MN, Wonder E, Kocherginsky M, et al. Glucocorticoid receptor antagonism as a novel therapy for triple negative breast cancer. Clinical Cancer Res. 2013;19(22):6163-6172. 2. Isikbay M, Otto K, Kregel S, et al. Glucocorticoid receptor activity contributes to resistance to androgen-targeted therapy in prostate cancer. Horm Cancer. 2014;5(2):72-89. Citation Format: Hazel Hunt, Joseph Belanoff, Thad Block, Stacie P. Shepherd. Preclinical efficacy of the selective GR antagonist, CORT125134 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3623. doi:10.1158/1538-7445.AM2017-3623