title: Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies.
abstract: OBJECTIVE
  Endometrial carcinoma (EC) is the sixth most common cancer in women and therapies are limited for advanced and recurrent disease. Patient-derived tumor xenograft (PDTX) models are becoming popular tools in translational research because of their histological and genetic similarity to the original tumors and the ability to predict therapeutic response to treatments. Here, we established and characterized a panel of 24 EC PDTX models which includes the major histological and genetic subtypes observed in patients.
  
  
  METHODS
  Fresh tumor tissues collected from primary, metastatic and recurrent type I and type II EC patients were engrafted in immunocompromised mice. Histology, vimentin, and cytokeratin expression were evaluated, together with Microsatellite instability (MSI), mutation profiling by Whole Exome Sequencing and copy number profiling by Whole Genome Low Coverage Sequencing. The efficacy of both PI3K and MEK inhibitors was evaluated in a model of endometrioid carcinoma harboring PTEN, PIK3CA and KRAS mutations.
  
  
  RESULTS
  We observed good similarity between primary tumors and the corresponding xenografts, at histological and genetic level. Among the engrafted endometrioid models, we found a significant enrichment of MSI and POLE mutated tumors, compared to non-engrafted samples. Combination treatment with NVP-BEZ235 and AZD6244 showed the possibility to stabilize the tumor growth in one model originated from a patient who already received several lines of chemotherapy.
  
  
  CONCLUSIONS
  The established EC PDTX models, resembling the original human tumors, promise to be useful for preclinical evaluation of novel combination and targeted therapies in specific EC subgroups.
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium; KU Leuven, Department of Oncology, Laboratory for Translational Genetics, B-3000 Leuven, Belgium; VIB, Vesalius Research Center (VRC), B-3000 Leuven, Belgium. Electronic address: Jeroen.Depreeuw@vib-kuleuven.be.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Depreeuw
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: Els.Hermans@uzleuven.be.
authors.forename: Els
authors.initials: E
authors.lastname: Hermans
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: Stefanie.Schrauwen@med.kuleuven.be.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Schrauwen
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: Daniela.Annibali@kuleuven.be.
authors.forename: Daniela
authors.initials: D
authors.lastname: Annibali
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: coenegrachtslieve@hotmail.com.
authors.forename: Lieve
authors.initials: L
authors.lastname: Coenegrachts
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: debby.thomas@med.kuleuven.be.
authors.forename: Debby
authors.initials: D
authors.lastname: Thomas
authors.affiliation: UCL - Université Catholique de Louvain, University Hospitals Saint-Luc, Division of Surgical Gynecology, Department of Surgery, B-1200 Brussel, Belgium. Electronic address: mathieu.luyckx@uclouvain.be.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Luyckx
authors.affiliation: UCL - Université Catholique de Louvain, University Hospitals Saint-Luc, King Albert II Institute Biolibrary, B-1200 Brussels, Belgium. Electronic address: ilse.gutierrez@uclouvain.be.
authors.forename: Ilse
authors.initials: I
authors.lastname: Gutierrez-Roelens
authors.affiliation: Department of Gynecology, AZ Groeninge Hospital, B-8500 Kortrijk, Belgium. Electronic address: David.Debruyne@azgroeninge.be.
authors.forename: David
authors.initials: D
authors.lastname: Debruyne
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: kkonings@SCKCEN.be.
authors.forename: Katrien
authors.initials: K
authors.lastname: Konings
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Translational Cell & Tissue Research, Department of Imaging and Pathology, B-3000 Leuven, Belgium. Electronic address: Philippe.Moerman@uzleuven.be.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moerman
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium. Electronic address: Ignace.Vergote@uzleuven.be.
authors.forename: Ignace
authors.initials: I
authors.lastname: Vergote
authors.affiliation: KU Leuven, Department of Oncology, Laboratory for Translational Genetics, B-3000 Leuven, Belgium; VIB, Vesalius Research Center (VRC), B-3000 Leuven, Belgium. Electronic address: Diether.Lambrechts@vib-kuleuven.be.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: KU Leuven - University of Leuven, University Hospitals Leuven, Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, B-3000 Leuven, Belgium; Gynaecological Oncology, Netherlands Cancer Institute-Antoni Van Leeuwenhoek, Amsterdam, The Netherlands. Electronic address: Frederic.Amant@uzleuven.be.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Amant
mesh_terms: D000818:Animals; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology*; D005260:Female; D006801:Humans; D051379:Mice; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
chemical_list: D047428:Protein Kinase Inhibitors
keywords: Endometrial cancer; Patient-derived tumor xenografts; Preclinical models; Targeted therapy