Abstract 5204: Morphology-guided classification of oral cancer using patient-derived organoids and its therapeutic implications

Abstract Oral cancer is an aggressive malignancy with a survival rate below 50% and a high rate of locoregional recurrence in advanced stages. The treatment method for patients with oral cancer is highly dependent on surgery and radiation, because there is still no therapeutic target due to the low mutation rate and the absence of molecular subtypes due to high tumor heterogeneity. Patient-derived organoid (PDO) is a good model that can overcome the limitations in translational study of oral cancer, as they reflect the characteristics of patient tissues at a high level and serve as a valuable preclinical model.In this study, we classified oral cancer into three subtypes based on patient-derived organoid (PDO) morphology and proposed new treatment strategies based on subtype-specific mutations and -transcriptional characteristics. First, we classified OSCC organoids into three distinct morphologies from successfully established 77 cancer and 81 normal oral cancer PDO libraries: normal-like, dense, and graph-like. Morphological subtypes were consistent with genomic mutations and transcriptome characteristics. Morphological subtypes were correlated not only with genomic mutations and transcriptomic characteristics, but especially with clinical recurrence prognosis. Patients with normal-like had a low mutation burden and a good prognosis, whereas patients with dense or grape-like had many mutations and a poor prognosis for recurrence. As a result of evaluating 14 drugs by organoid subtype in a high-throughput drug evaluation system using a 384-well plate, normal-like or grape-like organoids showed a good response to single drug treatment. We observed that dense organoids, which exhibited resistant responses to single drugs, showed an increased synergistic effect when co-treated with the first-line standard chemotherapy drug, cisplatin, and the ATR inhibitor (bay1895344), compared to other subtypes. Citation Format: Mi Rim Lee, sumin Kang, Jonghyun Lee, Sun-Young Kong, Yu-Sun Lee, Hye Won Shon, Gyeongmin Kang, Jiyoung Lee, Suk Min Youn, Da Woon Kwack, Joo Yong Park, Soung Min Kim, Wonyoung Choi, Jong-Ho Lee, Dongkwan Shin, Ik-Jae Kwon, Sung-Woen Choi, Yun-Hee Kim. Morphology-guided classification of oral cancer using patient-derived organoids and its therapeutic implications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5204.