Taya Manisha, Hou Xiaonan, Veneris Jennifer T, Kazi Nina, Larson Melissa C, Maurer Matthew J, Heinzen Ethan P, Chen Hao, Lastra Ricardo, Oberg Ann L, Weroha S John, Fleming Gini F, Conzen Suzanne D
Division of Hematology and Oncology, UT Southwestern, Dallas, TX, USA.
Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
J Gynecol Oncol. 2025 Jan;36(1):e4. doi: 10.3802/jgo.2025.36.e4. Epub 2024 Jun 14.
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).
Six high-grade serous (HGS) OvCa PDX models expressing GR mRNA () and protein were treated with chemotherapy +/- SGRM. Tumor size was measured longitudinally by peritoneal transcutaneous ultrasonography.
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.
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.
在卵巢癌（OvCa）中，肿瘤细胞高表达糖皮质激素受体（GR）与患者预后不良相关。在体外，GR激活可抑制化疗诱导的OvCa细胞死亡，并伴有抗凋亡蛋白编码基因的转录上调。最近一项随机II期研究表明，与单纯化疗相比，随机接受选择性GR调节剂（SGRM）加化疗的高度预处理OvCa患者的无进展生存期（PFS）有所改善。我们假设SGRM治疗可改善OvCa患者来源异种移植瘤（PDX）对卡铂的反应。
对6个表达GR mRNA和蛋白的高级别浆液性（HGS）OvCa PDX模型进行化疗±SGRM治疗。通过经皮腹膜超声纵向测量肿瘤大小。
6个GR阳性PDX模型中有1个在添加SGRM后PFS有显著改善。有趣的是，PFS改善的单一模型对卡铂最不敏感。SGRM活性适度的可能解释包括5个PDX肿瘤对卡铂高度敏感，以及SGRM可能激活患者体内的肿瘤侵袭性免疫细胞（免疫缺陷小鼠中不存在）。仅肿瘤GR蛋白表达水平似乎不足以预测SGRM反应。
6个模型中有1个在接受SGRM加化疗后PFS显著改善，这突出表明需要确定HGS OvCa中SGRM治疗的预测生物标志物，并更好地识别最有可能从化疗中添加GR调节中获益的患者亚组。
