Establishment and preclinical application of a patient-derived xenograft model for uterine cancer

• Published in: Gynecologic oncology 2021-07, Vol.162 (1), p.173-181
• Main Authors: Jeong, Soo Young, Cho, Young-Jae, Ryu, Ji-Yoon, Choi, Jung-Joo, Hwang, Jae-Ryoung, Kim, Binnari, Lee, Yoo-Young, Kim, Hyun-Soo, Lee, Jeong-Won
• Format: Article
• Language: English
• Subjects: Animals; Class I Phosphatidylinositol 3-Kinases - genetics; Class I Phosphatidylinositol 3-Kinases - metabolism; Female; Graft Survival; Heterografts; Humans; Mice; Neoplasm Staging; Neoplasm Transplantation; Orthotopic model; Patient-derived xenograft; Phosphatidylinositol 3-kinase inhibitor; Phosphoinositide-3 Kinase Inhibitors - pharmacology; Point Mutation; PTEN Phosphohydrolase - genetics; PTEN Phosphohydrolase - metabolism; Subrenal Capsule Assay - methods; Subrenal capsule implantation; Transplantation, Heterologous; Uterine cancer; Uterine Neoplasms - drug therapy; Uterine Neoplasms - genetics; Uterine Neoplasms - metabolism; Uterine Neoplasms - pathology
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2021.04.028

The patient-derived xenograft (PDX) model is a promising translational platform for duplicating the characteristics of primary tumors. Here, we established and characterized PDX models of uterine cancer to demonstrate their utility for preclinical drug testing. We generated PDX tumors surgically derived from 58 cases of uterine cancer. Subrenal capsule xenografts and primary tumors were compared using microscopic examination, short tandem repeat analyses, and targeted sequencing analyses. A phosphatidylinositol 3-kinase (PI3K) inhibitor was administered to mice whose PDX tumors harbored a PTEN deletion or PIK3CA mutation. We also generated an orthotopic PDX model using uterine horn implantation. Thirty-three (56.9%) PDXs were successfully generated and passaged to maintain tumors. The histological features of the PDX tumors were stable over subsequent passages. By contrast, the proportions of epithelial and mesenchymal components of carcinosarcoma PDX models varied by generation. Targeted sequencing analyses revealed that all mutated cancer-related genes were stable during establishment and subgrafting. Treatment with a PI3K inhibitor cased a significant decrease in tumor weight in the clear cell carcinoma PDX harboring a frameshift PTEN deletion (p = 0.049) and in the serous carcinoma PDX harboring a missense PI3KCA mutation (p = 0.003) compared with matched controls. We also successfully established orthotopic PDX models (3/3; 100.0%). The histological and genetic features of PDXs were similar to those of primary tumors. This model is a promising translational platform for preclinical testing of new anticancer drugs and will enable the personalized development of therapeutic options for uterine cancer. •We observed similar or higher engraftment rates of uterine cancer PDXs than those of previous studies.•The histological and genetic features of subrenal capsule PDXs were similar to those of primary tumors.•PDX models can be applied to predict clinical outcomes before the application of targeted therapies for patients.