Oncotarget

Research Papers:

Glucocorticoid receptor antagonism promotes apoptosis in solid tumor cells

Andrew E. Greenstein _ and Hazel J. Hunt

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Oncotarget. 2021; 12:1243-1255. https://doi.org/10.18632/oncotarget.27989

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Abstract

Andrew E. Greenstein1 and Hazel J. Hunt1

1 Corcept Therapeutics, Menlo Park, CA, USA

Correspondence to:

Andrew E. Greenstein,email: agreenstein@corcept.com

Keywords: glucocorticoid; tumors; apoptosis; chemotherapy; drug resistance

Received: March 28, 2021     Accepted: June 02, 2021     Published: June 22, 2021

Copyright: © 2021 Greenstein and Hunt. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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.


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