Abstract 1035: A comprehensive patient-derived tumor xenograft (PDX) collection representing the heterogeneity of kidney, prostate and bladder cancers

Abstract

Abstract Kidney, prostate and bladder cancers (KCa, PCa and BCa, respectively) represent 1 700 000 cases and 450 000 deaths worldwide per year, with an incidence rising yearly by 1-10%. Surgery is usually curative at early and localized stages but there are no efficient therapies at advanced and metastatic stages for any of them. Although genetically-modified and/or chemically-induced avatar models do exist for these cancers and may help to identify new therapeutic targets, they suffer from a lack of an extended biological concordance with the natural history and heterogeneity of the diseases. Patient-derived tumor xenograft models are now well recognized as reliably reproducing tumor heterogeneity and have become over the past few years the preclinical tools of choice to test drugs and identify biomarkers. Since 10 years, we are continuously developing a unique panel of PDX models for these major urological cancers. Tumor tissues along with normal corresponding tissues were obtained from patients at surgery. Patient informed consent and clinical history are available for all patients. Tumor tissues pieces were xenografted subcutaneously in the interscapular space of nude mice, and serially passaged into mice after the first engraftment, up to passage 10. To ensure model stability between primary tumors and tumors growing in mice but also from passage to passage, we performed various analyses at histopathological, genetic (short tandem repeat fingerprinting) and molecular (cDNA profiling) levels. In addition, growth characteristics and responses to standards of care (SOCs) were examined. Finally, specific molecular characteristics were also explored including expression of the androgen receptor, PSA and pan-cytokeratin for PCa models and hotspot mutations of FGFR3, PIK3CA, K/N/H-RAS for BCa models. Up to now, we have xenografted 336 (on 569 samples), 247 and 152 KCa, PCa and BCa tumor tissues, and developed 30 (8.9% success rate), 6 (2.1%) and 30 (19.7%) PDX models, respectively. We recently published part of the KCa PDX models collection (Lang et al., Oncotarget, 2016). Characterization studies showed that PDX models are stable at all levels analyzed considering concordance to primary tumors and from passage to passage; and less than 5% of genes were differentially expressed between the primary tumors and PDX tumors at various passages. Responses to SOCs recapitulated the clinical state. Only for KCa PDX models, the take rate was correlated to tumor stage and grade, and sarcomatoid components. Importantly, several molecular subtypes were defined in our collection of BCa PDX models including PDXs with FGFR3 mutations and PDXs of basal subtype, the most aggressive one. Overall, this panel of PDX models for urological cancers should definitely help to find molecularly guided targeted therapies for these still incurable cancers at metastatic stages. Citation Format: Hervé Lang, Claire Béraud, Myriam Lassalle, Isabelle Bernard-Pierrot, Véronique Lindner, Yves Allory, Michel Soulié, Xavier Gamé, Pascal Rischmann, Eric Potiron, François Radvanyi, Philippe Lluel, Thierry Massfelder. A comprehensive patient-derived tumor xenograft (PDX) collection representing the heterogeneity of kidney, prostate and bladder cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1035.