Patient-Derived Xenograft Mouse Model of a Rare Gynecologic Malignancy: Personalized Medicine for the Treatment of Mesonephric-Like Adenocarcinoma.

BACKGROUND: Mesonephric-like adenocarcinoma (MLA) is a rare malignant tumor that mainly occurs in the uterine body and ovaries and has characteristics similar to mesonephric adenocarcinoma in the uterine cervix. Although MLA has a poor clinical prognosis, no standard treatment for MLA has been developed, mainly because of its rarity. Here, we aimed to develop a precision medicine platform for MLA using a patient-derived xenograft (PDX) mouse model. METHODS: We established an MLA PDX mouse model via orthotopic implantation of a primary uterine tumor. Whole exome sequencing of the primary MLA tumor was performed to detect the genomic characteristics. For drug testing, we generated a patient-derived explant (PDE) model using sliced PDX tumors on medium-soaked gelatin sponges exposed to drugs. As another evaluation method, we cultured MLA cells from PDX tumors via a three-dimensional culture method with each drug treatment. Furthermore, we investigated the antitumor effects of a combination of trametinib and omipalisib compared with carboplatin in MLA PDX mice in vivo. RESULTS: MLA PDX tumors exhibited similar histological features to the original patient tumors. Whole exome sequencing revealedpathogenic variants ofKRAS and PIK3CA in the patient's tumor. In PDE and three-dimensional culture models, carboplatin, paclitaxel, trametinib, and omipalisib had antitumor effects on MLA compared with the control. In addition, the combination of trametinib and omipalisib significantly suppressed MLA PDX tumor growth compared with the control. CONCLUSIONS: We established a PDX model of MLA to facilitate personalized treatment for rare tumors.