Cancer Therapy: Preclinical Establishment and Characterization of a Panel of Human Uveal Melanoma Xenografts Derived from Primary and/or Metastatic Tumors Fariba Némati 1 , Xavier Sastre-Garau 2 , Cécile Laurent 3,4,14 , Jérôme Couturier 6 , Pascale Mariani 7 , Laurence Desjardins 8 , Sophie Piperno-Neumann 9 , Olivier Lantz 2 , Bernard Asselain 3,4,10,14 , Corine Plancher 10 , Delphine Robert 2 , Isabelle Péguillet 2 , Marie-Hélène Donnadieu 2 , Ahmed Dahmani 1 , Marie-Andrée Bessard 1 , David Gentien 11 , Cécile Reyes 12 , Simon Saule 5 , Emmanuel Barillot 3,4,14 , Sergio Roman-Roman 12 , and Didier Decaudin 1,13 Abstract Purpose: Uveal melanoma is the most common primary intraocular malignant tumor in adults and is de- fined by a poor natural outcome, as 50% of patients die from metastases. The aim of this study was to develop and characterize a panel of human uveal melanoma xenografts transplanted into immunodeficient mice. Experimental Design: Ninety tumor specimens were grafted into severe combined immunodeficient mice, and 25 transplantable xenografts were then established (28%). Relationship between tumor graft and clinical, biological, and therapeutic features of the patients included were investigated. Characterization of 16 xenografts included histology, molecular analyses by immunohistochemistry, genetic alteration anal- ysis (single-nucleotide polymorphism), and specific tumor antigen expression by quantitative reverse tran- scription-PCR. Pharmacologic characterization (chemosensitivity) was also done in four models using two drugs, temozolomide and fotemustine, currently used in the clinical management of uveal melanoma. Results: Take rate of human uveal melanoma was 28% (25 of 90). Tumor take was independent of size, histologic parameters, or chromosome 3 monosomy but was significantly higher in metastatic tumors. Interestingly, in vivo tumor growth was prognostic for a lower metastasis-free survival in patients with primary tumors. A high concordance between the patients' tumors and their corresponding xeno- grafts was found for all parameters tested (histology, genetic profile, and tumor antigen expression). Finally, the four xenografts studied displayed different response profiles to chemotherapeutic agents. Conclusions: Based on these results, this panel of 16 uveal melanoma xenografts represents a useful pre- clinical tool for both pharmacologic and biological assessments. Clin Cancer Res; 16(8); 2352–62. ©2010 AACR. Uveal melanoma is the most common primary intraoc- ular malignant tumor in adults. Despite the increased di- agnostic accuracy and the development of conservative and effective treatments on primary tumor sites, such as plaque radiotherapy and photon beam therapy, the mor- tality remains stable and 50% of patients die from metas- tases that frequently involve the liver. Chemotherapy, such as oral temozolomide and intra-arterial fotemustine used at the metastatic stage, induces very low response rates, 14.3% and 36%, respectively, and a median survival time of 6.7 and 15 months (1–3). No postoperative adjuvant therapies are currently available to decrease the risk of metastases. Several prognostic factors of dissemi- nated relapse after initial ophthalmologic treatment have been determined, including location with respect to the equator, monosomy 3, and retinal detachment (4). However, no effect of these prognostic markers on patient care can be envisaged in the absence of effective systemic therapies. The growing body of knowledge about molecular and genetics events involved in oncogenesis and tumor pro- gression has led to the identification of new therapeutic targets and therapeutic agents. Preclinical investigation in relevant models is therefore mandatory to select therapeu- tic agents before their assessment in clinical trials. To ob- tain preclinical results with high predictive value for Authors' Affiliations: 1 Laboratory of Preclinical Investigation, Translational Research Department, Institut Curie; 2 Department of Tumor Biology, Institut Curie; 3 Institut Curie; 4 Institut National de la Sante et de la Recherche Medicale, U900; 5 Centre National de la Recherche Scientifique UMR146, Institut Curie; 6 Department of Genetics, Institut Curie; 7 Department of Visceral Surgery, Institut Curie; 8 Department of Ophthalmological Oncology, Institut Curie; 9 Department of Medical Oncology, Institut Curie; 10 Department of Statistics, Institut Curie; 11 Affymetrix Platform, Translational Research Department, Institut Curie; 12 Translational Research Department, Institut Curie; 13 Department of Clinical Hematology, Institut Curie, Paris, France and 14 Ecole des Mines de Paris, Fontainebleau, France Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Corresponding Author: Didier Decaudin, Laboratoire d'Investigation Pré-clinique/Service d'Hématologie Clinique, Institut Curie, 26 rue d'Ulm, 75.248 Paris cedex 05, France. Phone: 33-1-44-32-46-90; Fax: 33-1-53-10-40-11; E-mail: didier.decaudin@curie.net. doi: 10.1158/1078-0432.CCR-09-3066 ©2010 American Association for Cancer Research. Clinical Cancer Research Clin Cancer Res; 16(8) April 15, 2010 2352 Research. on June 16, 2020. © 2010 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst April 14, 2010; DOI: 10.1158/1078-0432.CCR-09-3066 Research. on June 16, 2020. © 2010 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst April 14, 2010; DOI: 10.1158/1078-0432.CCR-09-3066 Research. on June 16, 2020. © 2010 American Association for Cancer clincancerres.aacrjournals.org Downloaded from Published OnlineFirst April 14, 2010; DOI: 10.1158/1078-0432.CCR-09-3066