Characterization of patient-derived tumor xenograft models of endometrial cancer for preclinical evaluation of targeted therapies

• Patient-derived tumor xenografts (PDTXs) can be established from endometrial cancer.
• Endometrial cancer PDTXs maintain the general features of the human tumor.
• Such models can be used as preclinical tools to study therapy response.

ObjectiveEndometrial 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.MethodsFresh 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.ResultsWe 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.ConclusionThe 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.

General overview of the establishment of endometrial PDTX models. Primary tumor tissue (F0) was surgically removed and implanted in mice. In parallel, remaining tissue was fresh-frozen and formalin-fixed for histological and genetic analysis. After engraftment (F1), tumor tissue was implanted in new mice for expansion (F2). Tumors were further transplanted in F3 generation for histological and genetic validation and compared with the primary tumor.Figure optionsDownload as PowerPoint slide