Abstract 2773: Development and characterization of a large panel of tumorgraft-based clinically relevant models derived from patients with kidney, bladder or prostate cancer.

Abstract

Abstract Kidney, bladder and prostate cancers are the 3 prevalent urological cancers. They represent each year 1 500 000 new cases and 500 000 deaths worldwide with an incidence increasing steadily by 2-10% per year. At advanced stages, current first-line therapies are inefficient. One of the major needs in new drugs development is the availability of a large panel of clinically pertinent models representing patients’ heterogeneity. In addition, our ability to tailor specific drugs to patients is restricted by the lack of validated biomarkers and might be considered as the most important barrier for a better clinical response. Kidney, bladder and prostate tumor tissues at all stages were collected from patients undergoing surgery, xenografted in nude mice, and serially passaged into new mice. All tumors were implanted subcutaneously and some of them orthotopically. Informed consent and clinical history were obtained for all patients. For all 3 cancer types, tissue samples from the patients’ primary tumor and tumors grown in mice through passages were analyzed for primary tumor-models stability by histopathology, mRNA expression profiling, growth behavior and response to first-line therapies (sunitinib/sorafenib/everolimus, cisplatin and docetaxel for kidney, bladder and prostate cancer respectively). In addition, for each cancer type and models derived from it, we also analyzed more specific tumor characteristics for their stability: the VHL status and the genetic stability by short tandem repeat fingerprinting for kidney cancer; the expression of interest genes including FGFR3, HRAS or p53 genes for bladder cancer, and the expression/mutations of the androgen receptor and the expression of prostate specific antigen and cytokeratin for prostate cancer. Orthotopic models were followed by infrared imaging after intravenous injection of the IR780 dye. So far and since 2007, we have xenografted 380 kidney tumors, 80 bladder tumors and 150 prostate tumors, out of which we have established 31, 11 and 3 models (passage above 3 and up to 12 in mice), respectively. The tumor take rate in mice (7.4% overall success) was significantly correlated with tumor stages, but not with any other tumor features. Importantly, tumors were stable through passages at the histopathologic, molecular and genetic levels. In addition, the responsiveness of tumors grown in mice to current therapies compounds was similar to patients’ therapeutic responses, also highlighting the clinical predictivity of our models. Orthotopic models developed metastases at classical secondary sites. We developed a unique platform of well characterized, stable and clinically predictive mouse xenograft urological cancer models. This is an invaluable tool for the clinical design of efficient therapies and for the identification of predictive biomarkers. Citation Format: Thierry Massfelder, Claire Beraud, Audrey Bethry, Sabrina Danilin, Véronique Lindner, Didier Jacqmin, Hervé Lang. Development and characterization of a large panel of tumorgraft-based clinically relevant models derived from patients with kidney, bladder or prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2773. doi:10.1158/1538-7445.AM2013-2773