J Gynecol Oncol.
2025 Jan;36(1):e4. 10.3802/jgo.2025.36.e4.
Investigation of selective glucocorticoid receptor modulation in high-grade serous ovarian cancer PDX models
- Taya M
1 - Hou X2
- Veneris JT3
- Kazi N1
- Larson MC4
- Maurer MJ4
- Heinzen EP5
- Chen H5
- Lastra R7
- Oberg AL8
- Weroha SJ2
- Fleming GF3
- Conzen SD1
- Affiliations
-
- 1Division of Hematology and Oncology, UT Southwestern, Dallas, TX, USA
- 2Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
- 3Department of Medicine, Section of Hematology and Oncology, The University of Chicago, Chicago, IL, USA
- 4Division of Clinical Trials and Biostatistics, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- 5Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
- 6Department of Pathology, UT Southwestern, Dallas, TX, USA
- 7Department of Pathology, The University of Chicago, Chicago, IL, USA
- 8Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA
- KMID: 2565446
- DOI: http://doi.org/10.3802/jgo.2025.36.e4
Abstract
Objective
In ovarian cancer (OvCa), tumor cell high glucocorticoid receptor (GR) has been associated with poor patient prognosis. In vitro, GR activation inhibits chemotherapyinduced 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.
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