Abstract 26: Developing PDX derived organoid models for efficacy evaluation of anticancer therapies

Abstract BACKGROUND AND PURPOSE: Developing the most fitting models that best reflect real patient tumor system is crucial for advancing cancer mechanistic research and mediating drug discovery. Patient derived xenograft (PDX) models can accurately reflect cancer responses to therapies, thus being recognized as a gold standard in oncology drug development. However, PDX models can be labor intensive, time-consuming and costly. Cancer organoid is 3D infinitesimal derived from cancer stem cells, which can faithfully recapitulate genetic profile, mutational landscape, phenotypic and histo-pathological features and responses to therapies of patient tumors. Organoids derived from PDX tumors, namely PDXOs, are suitable for in vitro anticancer drug efficacy evaluation, forming good combinations with their in vivo PDX counterparts. This work aims to develop PDXO models from our PDX biobank for anti-cancer drug efficacy evaluation uses. EXPERIMENTAL APPROACH: PDXOs were developed using Matrigel dome embedding approach with fresh cell digests from PDX tumor tissues. The model development included continuous expansion for >3 passages followed with cryopreservation and downstream analysis. Each model was assessed using bright field imaging (BFI) and H&E staining. Whole exome sequencing (WES) and mRNAseq were used to assess the genetic status. Immunocytochemical staining (ICC) and flow cytometry were used to assess the biomarker expression. CellTiter-Glo (CTG) assay and LDH release assay were used for drug efficacy evaluation. KEY RESULTS: By 2024-Oct, we have established >20 PDXOs, covering different cancer types, including colon cancer, gastric cancer, pancreatic cancer, lung cancer, liver cancer, etc. We have shown that the exonic mutational status and drug response behavior of PDX and PDXO counterparts were consistent, and CTG assay and BFI were suitable for drug efficacy evaluation of PDXOs. We have also shown that PDXOs with particular protein expression features were suitable for evaluating the corresponding targeted therapies. Moreover, co-culture with PBMCs or other immune cells could be used to assess the anti-cancer efficacy of immune therapies on PDXOs. CONCLUSIONS AND IMPLICATIONS: Our work illustrates the significant potential and value of PDXO models in assessing various kinds of anti-cancer therapies. An integrated platform combining PDX and PDXO models will advance cancer pharmacological research and drug discovery. Citation Format: Weizhong Zhang, Xinyi Zhao, Yufeng Chang, Yifei Jiang, Fan Jia, Zonghaoyu Sun, Jiahe Li, Xuehua Zhang, Xudong Yan, Qinjuan Zhou, Dengqing Zhang, Yunkun Guan, Xueli Mei, Fei Yan, Chen Zhao, Junle Liao, Zishi Liu, Qundi Mei, Jingxuan Zhang, Yuanyuan He, Xinyu Zhang, Jiewen Zhang, Wei Sun, Baohong Cao. Developing PDX derived organoid models for efficacy evaluation of anticancer therapies [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 26.