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Endometrial cancer PDX-derived organoids (PDXOs) and PDXs with FGFR2c isoform expression are sensitive to FGFR
Asmerom T Sengal1, Vanessa Bonazzi2,3, Deborah Smith4
1Endometrial Cancer Laboratory, School of Biomedical Sciences, Faculty of Health, the Queensland University of Technology located at the Translational Research Institute (TRI), PA Hospital Campus, 37 Kent St Woolloongabba, Brisbane, 4102, QLD, Australia. asmerom.sengal@qut.edu.au.
Abstract:
Endometrial cancer (EC) patients with metastatic/recurrent disease have limited treatment options and poor survival outcomes. Recently, we discovered the FGFR2c splice isoform is associated with poor prognosis in EC patients. Here we report the establishment of 16 EC patient-derived xenografts (PDX)-derived organoids (PDXOs) with or without FGFR2c expression. In vitro treatment of 5 EC PDXOs with BGJ398 showed significant cell death in 3 models with FGFR2c expression. PDXs with high/moderate FGFR2c expression showed significant tumour growth inhibition (TGI) following 21-day treatment with FGFR inhibitors (BGJ398 or pemigatinib) and significantly prolonged survival in 4/5 models. Pemigatinib + cisplatin combination therapy (n = 5) resulted in significant TGI and prolonged survival in one of two p53abn PDXs. All five models treated with cisplatin alone showed de novo resistance and no survival benefit. Seven-day treatment with BGJ398 revealed a significant reduction in angiogenesis and CD206 + M2 macrophages. These data collectively support the evaluation of FGFR inhibitors in a clinical trial.
Insights
Fibroblast growth factor receptor (FGFR) inhibitors show promise for treating advanced endometrial cancer (EC). Targeting FGFR2c in preclinical models reduced tumor growth and improved survival, suggesting clinical trial potential.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Advanced endometrial cancer (EC) presents limited therapeutic options and poor prognosis.
- The FGFR2c splice isoform has been identified as a marker of poor prognosis in EC patients.
Purpose of the Study:
- To evaluate the efficacy of FGFR inhibitors in preclinical models of endometrial cancer.
- To assess the role of FGFR2c expression in treatment response.
Main Methods:
- Establishment of 16 endometrial cancer patient-derived xenografts (PDX) and derived organoids (PDXOs).
- In vitro and in vivo treatment of PDXOs and PDXs with FGFR inhibitors (BGJ398, pemigatinib) and cisplatin.
- Assessment of tumor growth inhibition (TGI), survival, angiogenesis, and M2 macrophage infiltration.
Main Results:
- FGFR inhibitors demonstrated significant cell death in FGFR2c-expressing EC PDXOs.
- In vivo treatment with FGFR inhibitors led to significant TGI and prolonged survival in 4/5 PDX models with high/moderate FGFR2c expression.
- Cisplatin monotherapy showed de novo resistance, while combination therapy with pemigatinib showed efficacy in a subset of p53-abnormal models. FGFR inhibitor treatment reduced angiogenesis and M2 macrophages.
Conclusions:
- FGFR inhibitors are effective against endometrial cancer models expressing FGFR2c.
- FGFR inhibitors demonstrate preclinical efficacy, warranting clinical trials for advanced endometrial cancer.
