Introduction: Women with advanced endometrial cancer (EC) have limited effective therapies and very poor survival. We developed and validated a novel dual spatial BaseScope transcriptomic (DSBT) assay for the detection of the two FGFR2 splice isoforms in fixed tissues[1]. Using this assay, we reported isoform switching from the FGFR2b (epithelial) splice-isoform to the FGFR2c oncogenic-splice-isoform in 30-40 %ECs. FGFR2c was associated with shorter recurrence-free survival and disease-specific survival in both the discovery and confirmatory cohort[1,2].
Aim: To evaluate FGFR2c in EC patient-derived xenografts (PDXs) and organoids (PDOs) and assess the efficacy of BGJ398, a clinically approved FGFR inhibitor (FGFRi) either alone or in combination with PD-1i in these models.
Method: DSBT assay was used to detect FGFR2c expression in matched patient tumours, 24 EC PDX models and 20 PDOs[3,4]. In vitro drug screening either single or drug combination was performed in PDOs and viability was assessed using high image content using Live/Dead assay. The in vitro FGFRi, cisplatin alone or in combination were validated using PDX models in NSG mice. FGFRi alone or in combination with PD1i testing was performed in our novel tri-PDO culture (EC PDO/cancer-associated fibroblasts and immune cells) models.
Results: We identified 6 EC PDX and PDO models with high FGFR2c expression. In vitro testing showed significant cell death in PDOs with FGFR2c+ following FGFRi therapy. Except for one model with p53-mut, all were resistant to cisplatin. This result was validated in vivo and PDXs with FGFR2c+ showed significant tumour growth inhibition. Maximum tumour death was noted in TriPDO culture with FGFRi+PD1i in models with MSI-high but not in p53wt and p53mut. Multispectral IF and flow cytometry showed high CD8T cells infiltration following FGFRi+PD1i in MSI-high models. In conclusion, FGFRi +PD1i is a promising target therapy for EC patients and a clinical trial concept has been adopted.