Endometrial cancer PDX-derived organoids (PDXOs) and PDXs with FGFR2c isoform expression are sensitive to FGFR inhibition

Asmerom T Sengal; Vanessa Bonazzi; Deborah Smith; Cristian P Moiola; Rohan Lourie; Rebecca Rogers; Eva Colas; Antonio Gil-Moreno; Sophia Frentzas; Naven Chetty; Lewis Perrin; Pamela M Pollock

doi:10.1038/s41698-023-00478-6

Endometrial cancer PDX-derived organoids (PDXOs) and PDXs with FGFR2c isoform expression are sensitive to FGFR inhibition

NPJ Precis Oncol. 2023 Dec 8;7(1):127. doi: 10.1038/s41698-023-00478-6.

Authors

Asmerom T Sengal¹, Vanessa Bonazzi^{2

3}, Deborah Smith⁴, Cristian P Moiola⁵, Rohan Lourie⁴, Rebecca Rogers⁴, Eva Colas⁵, Antonio Gil-Moreno⁵, Sophia Frentzas^{6

7}, Naven Chetty⁸, Lewis Perrin⁸, Pamela M Pollock⁹

Affiliations

¹ Endometrial 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.
² Endometrial 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.
³ Frazer Institute, The University of Queensland, Brisbane, QLD, 4102, Australia.
⁴ Mater Pathology, Mater Health, Brisbane, QLD, Australia.
⁵ Biomedical Research Group in Gynaecology, Vall Hebron Institute of Research (VHIR), CIBERONC, 08035, Barcelona, Spain.
⁶ Department of Medical Oncology, Monash Health, Melbourne, VIC, Australia.
⁷ Faculty of Medicine, Nursing and Health Sciences and School of Clinical Sciences, Monash University, Melbourne, VIC, Australia.
⁸ Department of Gynaecologic Oncology, Mater Cancer Centre, Mater Health Services, Brisbane, QLD, Australia.
⁹ Endometrial 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. pamela.pollock@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.