Glucocorticoid receptor antagonism promotes apoptosis in solid tumor cells

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 microtubuletargeted 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.

High glucocorticoid receptor expression in the sarcomatous versus carcinomatous elements of Mullerian carcinosarcomas

“…Preliminary data from a Phase II study of relacorilant, a selective GR modulator, demonstrated an improvement in median progression-free survival for patients with platinum-resistant ovarian cancer who received the combination of intermittent relacorilant and nab-paclitaxel over nab-paclitaxel alone (5.6 months versus 3.8 months, p < 0.05) ( Colombo et al, 2021 ). Preclinical data suggest that the combination of paclitaxel and a glucocorticoid receptor antagonist may also be worthy of investigation in pancreatic cancer and breast cancer patients ( Greenstein and Hunt, 2021 , Skor et al, 2013 ). Future studies should elucidate the mechanistic role that high GR expression and activity may play in the aggressive nature of these gynecologic cancers, with the hope that new treatment strategies can be tested.…”

Genetically Engineered Human Pituitary Corticotroph Tumor Organoids Exhibit Divergent Responses To Glucocorticoid Receptor Modulators

“…In support of this notion, studies in several cancers that are driven by the dysregulation of these receptors, including leukemia, breast, prostate, lung and ovarian cancers, show promise of targeting the GR as a strategy for combination treatment [52, 53]. In addition, relacorilant induces apoptosis in vitro using pancreatic and ovarian cancer cell lines [54]. The pro-apoptotic effects of GR modulators are tissue specific and may be a result of targeting the apoptotic/cycle signaling pathways and genes such as Bcl2 [55].…”

A data mining and semantic analysis reveals novel insights into the genetic characteristics of the glucocorticoid receptor interactome

“…Through the transactivation of anti-inflammatory functions and the transrepression of pro-inflammatory genes, GCs exert their anti-inflammatory effects, taking part in regulating inflammation and other immune system processes (17). Among the target genes of GR regulating attributes, one can also find pro-apoptotic genes, mainly used in the treatment of lymphoid malignancies and other neoplasms (50,51). During developmental phases, GCs are involved in several fetal programming processes, resulting in differences between treated and untreated subjects in adult life.…”