Abstract B059: A patient-derived xenograft (PDX) orthotopic mouse model of rare gynecologic mesonephric-like adenocarcinoma as a platform of personalized medicine
Authors: Kinose Yasuto , Kasuya Kanako , Wang Yan , Koizumi Mai , Toda Aska , Nakamura Koji , Kawano Mahiru , Kodama Michiko , Hashimoto Kae , Sawada Kenjiro , Kimura Tadashi 
Published: March 2024

Abstract
Background: Mesonephric adenocarcinoma (MA) is an uncommon, HPV-independent, malignant neoplasm with mesonephric (Wolffian) differentiation that mainly occurs in the uterine cervix. Recently, mesonephric-like adenocarcinoma (MLA) is characterized as a rare tumor showing similar characteristics to MA in the uterine body and the ovary (WHO Classification of tumors Female Genital Tumors 5th Edition). Although no large-size epidemiological data are available for MA and MLA, a multi-institutional study showed that MA and MLA were aggressive subtypes, typically diagnosed at advanced stages, with a high rate of pulmonary recurrence (Pors J, et al. Am J Surg Pathol 2021;45:498–506). Because of the rarity, there are no cell lines, no in vitro/in vivo preclinical models, no clinical trials conducted as well as no standard treatment established for MA and MLA. To find a more effective treatment than standard chemotherapy (paclitaxel plus carboplatin), here we aim to develop a personalized medicine platform for MLA using the patient-derived xenograft (PDX) model. Methods: We collected a patient's MLA tumor arising from the left broad ligament during the surgery and orthotopically implanted it into nude mice. When the PDX tumor developed over 1000 mm3, we euthanize the mouse, harvested the tumor, minced it, and transplanted the PDX tumor chunks into other mice to expand the PDX tumors. To investigate genomic characterization, whole exome sequencing (WES) of the primary MLA tumor was performed. For drug testing, we performed a patient-derived explant (PDE) model using sliced PDX tumors on medium-soaked gelatin sponges exposed to the drug (paclitaxel, carboplatin, cisplatin, doxorubicin, trametinib (MEK inhibitor), and omipalisib (PI3K/mTOR inhibitor)) for 72 hours. As another assessment of drug efficacy, we sorted MLA cells from PDX tumors using magnet-based mouse cell depletion and incubated them in a 3D-organoid culture method with each treatment (paclitaxel, carboplatin, trametinib, omipalisib, and trametinib plus omipalisib) for 72 hours. In vivo anti-tumor effect was tested using the PDX mouse model (control, carboplatin, trametinib plus omipalisib). Results: We established a rare gynecologic MLA PDX model and the PDX tumors have been collected stably up to the eighth passage. PDX tumors represented similar histology to the original patient tumor. WES results showed KRAS and PIK3CA pathogenic variants from the patient's tumor. In PDE and 3D-organoid models, MLA showed a significant response to carboplatin, paclitaxel, omipalisib, and trametinib compared with the control. In vivo PDX model demonstrated the efficacy of a combination of trametinib plus omipalisib. Conclusion: We made a PDX model of MLA and utilized the PDX for personalized medicine. Based on the driver genes, KRAS and PIK3CA, we found a combination of trametinib plus omipalisib is an effective treatment for MLA. This PDX-based method helps us to find effective therapeutics for many types of rare cancer.
Citation Format: Yasuto Kinose, Kanako Kasuya, Yan Wang, Mai Koizumi, Aska Toda, Koji Nakamura, Mahiru Kawano, Michiko Kodama, Kae Hashimoto, Kenjiro Sawada, Tadashi Kimura. A patient-derived xenograft (PDX) orthotopic mouse model of rare gynecologic mesonephric-like adenocarcinoma as a platform of personalized medicine [abstract]. In: Proceedings of the AACR Special Conference on Ovarian Cancer; 2023 Oct 5-7; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_2):Abstract nr B059.