Introduction/Background Alternative treatment options for endometrial cancer (EC) when chemotherapy fails are few. We have previously demonstrated the prognostic impact of Androgen receptor (AR) expression in EC (Tangen et al., 2016). However, the therapeutic potential of targeting AR in EC is not known. Patient-derived cancer organoids have recently developed as valuable tools for drug testing as they better represent the genetic background of the patient cohort. We recently reported a collection of patient-derived EC organoids (Berg et al., 2021), and have expanded this series to include models with distinct pattern of hormone receptor (HR) expression. Here we report preliminary data on the therapeutic effect on targeting AR and ER signaling pathways in a panel of EC organoids representing all subtypes and molecular subgroups of EC.

Methodology Patient-derived EC organoid models, representing the main histological subtypes of EC and distinct patterns of HR expression, were treated both short-term (48 hours) and long-term (18 days) with AR and ER agonists, R1881 and Estradiol, and the AR and ER antagonists, Enzalutamide and Fulvestrant. Response to treatment was evaluated using CellTiter-Glo 3D assay and Incucyte Live Cell System. Protein expression of AR and ER pre- and post-treatment was evaluated by immunohistochemistry.

Results EC organoid models with distinct hormonal expression of AR and ER showed model-specific response to short-term exposure to hormonal therapy. Modulation of expression and nuclear translocation of AR and ER were seen in several models after long-term exposure, also without affecting proliferation.

Conclusion Data indicates that targeting AR and ER pathways in EC is model specific, suggesting context-dependent signaling. Lack of measured effect on proliferation combined with altered HR expression in some models might point to clonal selection in response to HR activation.