Glucocorticoid receptor antagonism promotes apoptosis in solid tumor cells.

Andrew E Greenstein,Hazel J Hunt

doi:10.18632/oncotarget.27989

Andrew E Greenstein, Hazel J Hunt

Open Access

https://doi.org/10.18632/oncotarget.27989

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Journal: Oncotarget	Publication Date: Jun 22, 2021
Citations: 15	License type: cc-by

Affiliation: Corcept Therapeutics (United States)

Abstract

Background: Resistance to antiproliferative chemotherapies remains a significant challenge in the care of patients with solid tumors. Glucocorticoids, including endogenous cortisol, have been shown to induce pro-survival pathways in epithelial tumor cells. While pro-apoptotic effects of glucocorticoid receptor (GR) antagonism have been demonstrated under select conditions, the breadth and nature of these effects have not been fully established.Materials and Methods: To guide studies in cancer patients, relacorilant, an investigational selective GR modulator (SGRM) that antagonizes cortisol activity, was assessed in various tumor types, with multiple cytotoxic combination partners, and in the presence of physiological cortisol concentrations.Results: In the MIA PaCa-2 cell line, paclitaxel-driven apoptosis was blunted by cortisol and restored by relacorilant. In the OVCAR5 cell line, relacorilant improved the efficacy of paclitaxel and the potency of platinum agents. A screen to identify optimal combination partners for relacorilant showed that microtubule-targeted agents consistently benefited from combination with relacorilant. These findings were confirmed in xenograft models, including MIA PaCa-2, HeLa, and a cholangiocarcinoma patient-derived xenograft. In vivo, tumor-cell apoptosis was increased when relacorilant was added to paclitaxel in multiple models.Conclusions: These observations support recently reported findings of clinical benefit when relacorilant is added to paclitaxel-containing therapy in patients with ovarian and pancreatic cancers and provide a new rationale for combining relacorilant with additional cytotoxic agents.

Highlights

Drug resistance, whether primary or acquired, is a major impediment to cancer therapy
In the MIA PaCa-2 cell line, paclitaxel-driven apoptosis was blunted by cortisol and restored by relacorilant
Tumor-cell apoptosis was increased when relacorilant was added to paclitaxel in multiple models

Summary

Introduction

Whether primary or acquired, is a major impediment to cancer therapy. For both targeted agents and older chemotherapies, initial reductions in tumor volume typically have limited duration and are followed by the growth of drug-tolerant tumors. Glucocorticoids (GC), including endogenous cortisol, have been shown to induce prosurvival pathways in epithelial tumor cells [4,5,6]. Elevated cortisol activity has been implicated in the pathophysiology of multiple cancer types, but even normal physiological levels achieve GR agonism [7]. GR agonism could contribute to tumor cell biology even in patients with normal cortisol levels. Glucocorticoids, including endogenous cortisol, have been shown to induce pro-survival pathways in epithelial tumor cells. While pro-apoptotic effects of glucocorticoid receptor (GR) antagonism have been demonstrated under select conditions, the breadth and nature of these effects have not been fully established

Methods

Results

Conclusion