Abstract B080: Assessing the response of 3D human pancreatic tumor explants to standard chemotherapy

Abstract Background and aims: Pancreatic cancer (PC) patients have a dismal 11% 5-year survival rate. Therapy personalization has significant potential to improve this. Our team developed a world-first model to maintain and treat 3D pieces of human PC tissue in a dish (Kokkinos et al, Scientific Reports, 2021). To examine potential translation to precision medicine, this project aimed to: (1) assess explant response to PC chemotherapies; (2) develop a secretions-based approach for rapid measurement of explant response; (3) demonstrate the utility of our model to identify chemoresistance pathways. Methods: 27 patient-derived pancreatic tumor samples were obtained from surgical resections (Prof Haghighi; Prince of Wales hospital), then processed into 1-8mm3 explants. Explants were treated every 72h over 12 days, with the following drug combinations (used in neoadjuvant/adjuvant clinical setting): (i) Gemcitabine+5-fluorouracil (5-FU), (ii) Gemcitabine+Abraxane, (iii) 5-FU+Oxaliplatin+Irinotecan. Secretions were collected at endpoint for analysis of cancer and CAF-secreted markers by multiplex ELISA. Explants were fixed at endpoint for immunohistochemistry analysis of tumor cell/cancer-associated fibroblast (CAF) populations, cell death and proliferation, collagen content and spatial transcriptomics. Results: (1) Patient/regimen-dependent responses in tumor cell and CAF populations were observed. FOLFIRINOX was the most effective treatment (based on >50% reduction in tumor cells), followed by Gemcitabine+Abraxane and Gemcitabine+5FU, consistent with clinical trends. Patient/regimen-dependent explant responses to chemotherapy were also observed for CAF, cell death and proliferation markers, and collagen content. Follow up of patient overall survival is ongoing. (2) CA19-9 and IL6 were the most highly secreted markers and could follow changes in tumor and CAF populations. (3) Spatial transcriptomics identified differentially expressed genes in treatment-resistant tumor cells. Conclusions: Patient-derived explants demonstrate patient heterogeneity in response to standard chemotherapies and can be used to identify drug resistance pathways. Explant secretions can also be utilized to obtain an early indication of therapeutic response in culture. Citation Format: George Sharbeen, Janet Youkhana, Keilah G. Netto, Aparna S. Raina, Shannon Chiang, Koroush S. Haghighi, John Kokkinos, Omali Pitiyarachchi, Jessica Yang, Tony Wang, Alexander Swarbrick, David Goldstein, Phoebe A. Phillips. Assessing the response of 3D human pancreatic tumor explants to standard chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B080.