Jeroen Depreeuw1, Els Hermans2, Stefanie Schrauwen3, Daniela Annibali4, Lieve Coenegrachts5, Debby Thomas6, Mathieu Luyckx7, Ilse Gutierrez-Roelens8, David Debruyne9, Katrien Konings10, Philippe Moerman11, Ignace Vergote12, Diether Lambrechts13, Frédéric Amant14. 1. 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. 2. 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. 3. 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. 4. 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. 5. 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. 6. 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. 7. 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. 8. UCL - Université Catholique de Louvain, University Hospitals Saint-Luc, King Albert II Institute Biolibrary, B-1200 Brussels, Belgium. Electronic address: ilse.gutierrez@uclouvain.be. 9. Department of Gynecology, AZ Groeninge Hospital, B-8500 Kortrijk, Belgium. Electronic address: David.Debruyne@azgroeninge.be. 10. 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. 11. 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. 12. 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. 13. 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. 14. 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.
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. CONCLUSION: 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.
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 ECpatients 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. CONCLUSION: The established EC PDTX models, resembling the original humantumors, promise to be useful for preclinical evaluation of novel combination and targeted therapies in specific EC subgroups.
Authors: Anneliese Fortuna-Costa; Regina Alcantara Granato; Walter Meohas; Ana Cristina de Sá Lopes; Anabela Cunha Caruso; Rafael Castro E Silva Pinheiro; Pedro da Gama d'Eça; Rhayra Braga Dias; Jamila Alessandra Perini; Ana Paula Fernandes Barbosa; Renato Augusto Moreira de Sá; João Antonio Matheus Guimarães; Samuel S Murray; Maria Eugenia Leite Duarte Journal: Histol Histopathol Date: 2020-09-23 Impact factor: 2.303
Authors: Gonda Fj Konings; Niina Saarinen; Bert Delvoux; Loes Kooreman; Pasi Koskimies; Camilla Krakstad; Kristine E Fasmer; Ingfrid S Haldorsen; Amina Zaffagnini; Merja R Häkkinen; Seppo Auriola; Ludwig Dubois; Natasja Lieuwes; Frank Verhaegen; Lotte Ejr Schyns; Roy Fpm Kruitwagen; Sofia Xanthoulea; Andrea Romano Journal: Int J Mol Sci Date: 2018-08-28 Impact factor: 5.923
Authors: Cristian P Moiola; Carlos Lopez-Gil; Silvia Cabrera; Angel Garcia; Tom Van Nyen; Daniela Annibali; Tina Fonnes; August Vidal; Alberto Villanueva; Xavier Matias-Guiu; Camilla Krakstad; Frédéric Amant; Antonio Gil-Moreno; Eva Colas Journal: Int J Mol Sci Date: 2018-08-17 Impact factor: 5.923
Authors: Alyssa M Fedorko; Tae Hoon Kim; Russell Broaddus; Rosemarie Schmandt; Gadisetti V R Chandramouli; Hong Im Kim; Jae-Wook Jeong; John I Risinger Journal: Heliyon Date: 2020-05-27
Authors: Vanessa F Bonazzi; Olga Kondrashova; Deborah Smith; Katia Nones; Asmerom T Sengal; Robert Ju; Leisl M Packer; Lambros T Koufariotis; Stephen H Kazakoff; Aimee L Davidson; Priya Ramarao-Milne; Vanessa Lakis; Felicity Newell; Rebecca Rogers; Claire Davies; James Nicklin; Andrea Garrett; Naven Chetty; Lewis Perrin; John V Pearson; Ann-Marie Patch; Nicola Waddell; Pamela M Pollock Journal: Genome Med Date: 2022-01-10 Impact factor: 11.117