Next-generation cancer organoids 2.0 in precision cancer medicine: Patient-derived pancreatic ductal adenocarcinoma organoids model to describe drug sensitivity and complexity of tumor biology.

Abstract

4221 Background: Organotypic models of patient-specific tumors are revolutionizing our understanding of cancer heterogeneity and its implications for personalized medicine. The study's aims were as follows: 1) to establish a PDAC patient-derived organoid (PDO) model obtained from various PDAC specimens. 2) to find out clinicogenomic factors affecting patients’ outcomes. Methods: The SMC PDAC Cohort Patients were prospectively enrolled and underwent EUS-guided FNB, metastatic sites (such as liver, ascites, lung, and bone), and surgical resection. PDAC PDOs were comprehensively analyzed for histology, next generation sequencing (NGS), and high-throughput screening (HTS) drug sensitivity tests. Results: The 735 PDAC patients were prospectively enrolled in this study. PDAC PDO platform has been trying to establish from the following cancer specimens: ascites, biopsies from bone, liver, lung, and pancreas, or surgical resection. The success rate was as follows according to the source of obtaining site; ascites due to peritoneal seeding (3/3: 100%), bone mets (1/1: 100%), EUS-FNB (195/183: 87.8%), liver mets (7/8: 87.5%), lung mets (1/1: 100%), surgical specimens (394/500: 78.8%) and PDO was successfully established within 8.2±2.6 days. It took approximately 3 weeks to acquire each specimen and generate sufficient PDAC PDOs for the simultaneous HTS drug sensitivity test and NGS. Whole exome or genome sequencing (WES/WGS, n = 357) showed an almost identical concordance between original PDAC tissues and matched PDOs and the increased frequency of genetic alterations in PDOs. The HTS drug sensitivity test (n = 151) revealed the clinical correlation between the PDO response and the actual chemotherapeutic response of the study patients in both palliative and adjuvant in real-world settings (ranging from 84.0~ to 91.2%). In addition, whole transcriptome sequencing (n = 373) identified nab-paclitaxel resistance-associated genes such as ITGB7, ANPEP, and ST3GAL1, and also found early recurrence-related genes including COL2A1, CALB1, and CYP24A1 in the extracellular matrix, calcium signaling, and vitamin D metabolism. Conclusions: The PDAC PDO platform may become a valuable tool for personalized medicine and may give us insights into tumor biology.