Abstract B008: Ex-vivo organotypic tumor model of metastatic core biopsy serve as a pragmatic platform for real-time personalized therapy in pancreatic adenocarcinoma

Background: Metastases are common in patients with pancreatic ductal adenocarcinoma (PDAC) and are often associated with a significantly poorer prognosis. Current tissue-based models for personalized therapy, such as patient derived organoids or xenografts, remain technically and logistically burdensome. To address this critical need, we have developed a pragmatic ex vivo organotypic tumor model from core biopsies of metastases with testable and replicable conditions as a potential avenue for evaluating sensitivity to neoadjuvant chemotherapies. Methods: Standard-of-care image-guided 16G core biopsies of metastases were obtained from patients with PDAC undergoing clinically indicated biopsies through our Surgical Oncology Tissue Bank protocol. 3mm-4mm cut slices of cores were grown in sterile RPMI media on cell culture inserts in 24-well plates, with every 2 day media changes for a minimum of five days. Viability was assessed with a colorimetric MTS assay. After incubation with control or investigational agents, slices were fixed in formalin and examined using H&E and immunohistochemistry (IHC). Results: 10 core biopsies were obtained and processed (7 liver, 2 peritoneum, 1 lung) from March to June 2025; median number of 3mm slices created per sample was 5.5 [range 2-17]. All patients' samples had viable tumor in control conditions at 48 hours or greater confirmed on MTS and H&E stains. Based on individual patient’s known prior sensitivity to first or second-line chemotherapy, we tested a range of chemotherapeutic treatments (e.g. FOLFIRINOX, gemcitabine/paclitaxel) and targeted agents (e.g. pan-RAS inhibitor RMC-7977 and MEK inhibitor trametinib) against negative control (DMSO). In one patient with KRAS q61h mutation and known resistance to FOLFIRINOX (developed liver metastasis after 8 cycles of neoadjuvant therapy), 48 hour incubation experiment demonstrated MTS viability of 111% for FOLFIRINOX (compared to negative control), vs. 74% for gem/paclitaxel and interestingly 53% for RMC-7977. In another metastatic patient with KRAS wildtype and BRAF V487 mutation and long-term control of liver disease on FOLFIRINOX, 48 hour incubation demonstrated viability of 5% for FOLFIRINOX and 19% for trametinib; interestingly, this patient was subsequently switched to a MEK inhibitor and demonstrated normalization of CA19-9 after 2 months of targeted therapy. Quantification of tumor microenvironment dynamics are underway with IHC for cleaved caspase-3, Ki-67, and CD45. Conclusions: Our organotypic tumor culture system using patient-derived core biopsies represents a novel and pragmatic approach to real-time personalized therapy in metastatic PDAC. While it relies on presumed homogeneity of tissue across the core biopsy, this system is cost-effective, does not rely on take rate (as in organoids or xenograft models), and allows for preliminary viability readouts within days of biopsy. Further work is ongoing to validate viability signals with protein signals in fixed tissue, as well as comparisons to matured patient outcome and treatment data. Citation Format: Naveen Chandrashekhar, Jason Yuan, Natalie Stasny, Mohammed Aldakkak, Mandana Kamgar, Thomas McFall, Nikki Lytle, Jenny Grewal, Anna Stark, Olivia Guerra, Alexandria Phan, William A. Hall, Beth A. Erickson, Anai Kothari, Callisia N. Clarke, Kathleen Christians, William Rilling, Parag Tolat, Douglas B. Evans, Yongwoo D. Seo. Ex-vivo organotypic tumor model of metastatic core biopsy serve as a pragmatic platform for real-time personalized therapy in pancreatic adenocarcinoma [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): nr B008.