Generation and Integrated Analysis of Advanced Patient‐Derived Orthoxenograft Models (PDOX) for the Rational Assessment of Targeted Therapies in Endometrial Cancer

• Published in: Advanced science 2023-01, Vol.10 (1), p.e2204211-n/a
• Main Authors: Devis‐Jauregui, Laura, Vidal, August, Plata‐Peña, Laura, Santacana, Maria, García‐Mulero, Sandra, Bonifaci, Nuria, Noguera‐Delgado, Eulàlia, Ruiz, Nuria, Gil, Marta, Dorca, Eduard, Llobet, Francisco J., Coll‐Iglesias, Laura, Gassner, Katja, Martinez‐Iniesta, Maria, Rodriguez‐Barrueco, Ruth, Barahona, Marc, Marti, Lola, Viñals, Francesc, Ponce, Jordi, Sanz‐Pamplona, Rebeca, Piulats, Josep M., Vivancos, Ana, Matias‐Guiu, Xavier, Villanueva, Alberto, Llobet‐Navas, David
• Format: Article
• Language: English
• Subjects: Biomarkers; Biopsy; Cancer therapies; Chemotherapy; Endometrial cancer; HER2; Medical prognosis; Metastasis; Morphology; Patients; patient‐derived orthoxenografts; PDOX; Radiation therapy; Surgery; targeted therapies; Tumors
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202204211

Clinical management of endometrial cancer (EC) is handicapped by the limited availability of second line treatments and bona fide molecular biomarkers to predict recurrence. These limitations have hampered the treatment of these patients, whose survival rates have not improved over the last four decades. The advent of coordinated studies such as The Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (TCGA_UCEC) has partially solved this issue, but the lack of proper experimental systems still represents a bottleneck that precludes translational studies from successful clinical testing in EC patients. Within this context, the first study reporting the generation of a collection of endometrioid‐EC‐patient‐derived orthoxenograft (PDOX) mouse models is presented that is believed to overcome these experimental constraints and pave the way toward state‐of‐the‐art precision medicine in EC. The collection of primary tumors and derived PDOXs is characterized through an integrative approach based on transcriptomics, mutational profiles, and morphological analysis; and it is demonstrated that EC tumors engrafted in the mouse uterus retain the main molecular and morphological features from analogous tumor donors. Finally, the molecular properties of these tumors are harnessed to assess the therapeutic potential of trastuzumab, a human epidermal growth factor receptor 2 (HER2) inhibitor with growing interest in EC, using patient‐derived organotypic multicellular tumor spheroids and in vivo experiments. A new system to advance treatment options for endometrial cancer patients is reported. This model is based on the establishment of patient avatars through orthotopic engraftments in the mouse uterus. The morphological, transcriptomic, and DNA mutation analyses evidence that primary tumors and avatars exhibit multiscale resemblance and demonstrate that human epidermal growth factor receptor 2, HER2R678Q‐mutated tumors can be targeted in vivo with trastuzumab.