Investigation of selective glucocorticoid receptor modulation in high-grade serous ovarian cancer PDX models.

Autor:	Taya M; Division of Hematology and Oncology, UT Southwestern, Dallas, TX, USA., Hou X; Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA., Veneris JT; Department of Medicine, Section of Hematology and Oncology, The University of Chicago, Chicago, IL, USA., Kazi N; Division of Hematology and Oncology, UT Southwestern, Dallas, TX, USA., Larson MC; Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Maurer MJ; Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Heinzen EP; Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA., Chen H; Department of Pathology, UT Southwestern, Dallas, TX, USA., Lastra R; Department of Pathology, The University of Chicago, Chicago, IL, USA., Oberg AL; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA., Weroha SJ; Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA., Fleming GF; Department of Medicine, Section of Hematology and Oncology, The University of Chicago, Chicago, IL, USA., Conzen SD; Division of Hematology and Oncology, UT Southwestern, Dallas, TX, USA. suzanne.conzen@utsouthwestern.edu.
Jazyk:	angličtina
Zdroj:	Journal of gynecologic oncology [J Gynecol Oncol] 2024 Jun 14. Date of Electronic Publication: 2024 Jun 14.
DOI:	10.3802/jgo.2025.36.e4
Abstrakt:	Objective: In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapy-induced OvCa cell death in association with transcriptional upregulation of genes encoding anti-apoptotic proteins. A recent randomized phase II study demonstrated improvement in progression-free survival (PFS) for heavily pre-treated OvCa patients randomized to receive therapy with a selective GR modulator (SGRM) plus chemotherapy compared to chemotherapy alone. We hypothesized that SGRM therapy would improve carboplatin response in OvCa patient-derived xenograft (PDX). Methods: Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA ( NR3C1 ) and protein were treated with chemotherapy +/- SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography. Results: One of the 6 GR-positive PDX models showed a significant improvement in PFS with the addition of a SGRM. Interestingly, the single model with an improved PFS was least carboplatin sensitive. Possible explanations for the modest SGRM activity include the high carboplatin sensitivity of 5 of the PDX tumors and the potential that SGRMs activate the tumor invasive immune cells in patients (absent from immunocompromised mice). The level of tumor GR protein expression alone appears insufficient for predicting SGRM response. Conclusion: The significant improvement in PFS shown in 1 of the 6 models after treatment with a SGRM plus chemotherapy underscores the need to determine predictive biomarkers for SGRM therapy in HGS OvCa and to better identify patient subgroups that are most likely to benefit from adding GR modulation to chemotherapy. Competing Interests: JTV is currently an employee of GlaxoKlineSmith. GFF reports honorarium for talk from Curio Science, advisory board for GSK, uncompensated advisory board for TTC, and PI of industry-sponsored study for Corcept, Abbvie, Genentech/Roche, Tesaro/GSK, Syndax, 47 inc, Iovance, Syros, Astex, Merck, Sanofi, Sermonix, Compugen, INcyte, Hoffman LaRoche, Eisai. The authors acknowledge supply of Relacorilant from Corcept Therapeutics. SDC and The University of Chicago have been issued patents on methods of measuring GR expression in triple-negative breast cancer (TNBC) and using GR antagonists in TNBC and prostate cancer. (© 2025. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology, and Japan Society of Gynecologic Oncology.)
Databáze:	MEDLINE
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