Abstract A24: Establishment of a panel of patient-derived tumor xenograft models recapitulating molecular heterogeneity and drug response of muscle-invasive bladder tumors
Authors: Béraud Claire , Lang Hervé , Lassalle Myriam , Lindner Véronique , Kamoun Aurélie , Soulié Michel , Guillon Elodie , Krucker Clémentine , Gamé Xavier , Rischmann Pascal , De Reynies Aurélien , Allory Yves , Radvanyi François , Lluel Philippe , Massfelder Thierry , Bernard-Pierrot Isabelle 
Published: August 2020

Background: Muscle-invasive bladder cancers (MIBCs) constitute a heterogeneous group of tumors with poor outcome. Recently, MIBC molecular subtyping efforts from an international consortium led to the identification of six subtypes, improving prediction of clinical outcomes and treatment responses. FGFR3 alterations (mutations and translocations), observed in 20% of MIBCs, are found mainly in the luminal papillary subtype that respond poorly to chemo- and immunotherapy. Basal tumors represent 35% of MIBCs and were shown to be better responders to chemotherapy. Here, we describe the development and characterization of patient-derived primary MIBC xenografts (PDX) belonging to these main subtypes.

Methods: Bladder tumors were obtained from patients at surgery. Tumor fragments were subcutaneously engrafted into immune-compromised mice. Primary tumors and matched PDX tumors at multiple passages were analyzed regarding growth characteristics, histopathology (H&E staining, CK5/6, FOXA1, and GATA3 immunohistochemistry), gene expression (Affymetrix U133 plus 2.0 microarray), and genetic stability (STR profiling). Hotspot oncogenic mutations for FGFR3, PIK3CA, HRAS, KRAS, NRAS, PPARG, and RXRA were also assessed. Additionally, pharmacologic responses to standard-of-care and targeted therapies were characterized.

Findings: From 152 MIBC tumors at all stages and grades, 32 PDX models were successfully established (21.1% success rate). This take rate did not seem correlated to any classical tumor characteristics. Importantly, transcriptomic analysis allowed us to identify PDX models belonging to different molecular subtypes, notably the basal-like and luminal papillary subtypes, including PDXs with FGFR3 mutations. All histologic, genetic, and molecular features validated the stability of the PDX models compared to the parental tumors. Histologic analyses correlated with the molecular classification. These models reproduced the response to cisplatin-based therapies observed in the clinic. Basal models, except one harboring a FGFR3 mutation, were sensitive to anti-EGFR therapies but to a lesser extent than to chemotherapy. FGFR3-mutated PDX models, including a basal model, were highly responsive to FGFR3 inhibitors and less responsive to chemotherapy.

Conclusion: We have developed and characterized highly relevant preclinical models for MIBCs, including basal and FGFR3-mutated tumors, recapitulating molecular heterogeneity and drug responses as observed in patients with MIBCs. They represent essential tools for developing new, efficient therapies against this deadly disease.

Citation Format: Claire Béraud, Hervé Lang, Myriam Lassalle, Véronique Lindner, Aurélie Kamoun, Michel Soulié, Elodie Guillon, Clémentine Krucker, Xavier Gamé, Pascal Rischmann, Aurélien De Reynies, Yves Allory, François Radvanyi, Philippe Lluel, Thierry Massfelder, Isabelle Bernard-Pierrot. Establishment of a panel of patient-derived tumor xenograft models recapitulating molecular heterogeneity and drug response of muscle-invasive bladder tumors [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2019 May 18-21; Denver, CO. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(15_Suppl):Abstract nr A24.