Abstract 4234: Personalized therapeutic screening in patient derived organoids for gastroenteropancreatic neuroendocrine tumors

Abstract

Abstract Introduction Gastroenteropancreatic Neuroendocrine Neoplasms (GEP-NENs) are a rare subset of cancers which nevertheless are a rising health burden. Development of new therapies suffers from several bottlenecks, including low patient accrual and poor understanding of tumor characteristics. Patient tumor organoids (PTOs) are a novel model capable of improving screening of patient tissue in an accurate, standardized, and high-throughput capacity. In this study, we utilized patient tumors for creation of high-fidelity PTOs from a variety of GEP-NEN primary origins to evaluate therapy responses. Methods Tumors from patients undergoing clinically guided surgeries were processed within two hours of resection and dissociated into single-cell suspension. Cells were encapsulated into Matrigel and cultured into two groups. The first group was grown for 10 days to assess viability then treated with a panel of clinically approved therapies and novel treatments recommended by high throughput NEN cell line screening for treatment sensitivity using the MIPE 5.0 library. The second group was grown for long-term expansion and biobanking, followed by characterization using immunohistochemistry and genetic profiling to ensure tumor cell maintenance. Results From March 2023-November 2023, 14 patients provided 30 tumors for PTO development. These included small intestine (n=5), pancreatic (n=8), and gastric (n=1) neuroendocrine tumors. Long-term culture (>3 passages) was successful for 23/30 (77%) specimens, with passage timing related to tumor grade. PTOs maintained immunohistochemical characteristics of the parent tumor types and demonstrated similar genetic profiles, including neuroendocrine tumor cell markers synaptophysin, chromogranin A, and matched grade-based Ki67 proliferative index. The early-stage therapeutic screening was performed for 12/14 (86%) patients, demonstrating tumor grade dependent treatment efficacy and showing clinically dose relevant sensitivity towards approved small molecule inhibitor therapies including cabozantinib and sunitinib in a patient and tumor origin-dependent manner. Testing of effective therapy classes recommended by cell line treatment panels suggested high level treatment efficacy for proteosome inhibitors, MEK inhibitors, and topoisomerase inhibitors. Conclusion Development of GEP-NEN PTOs is feasible for long term culture and standard of care therapy testing. Further study demonstrated the successful application of novel therapeutic options in PTOs for patients with GEP-NENs. Citation Format: Steven D. Forsythe, Srujana V. Yellapragada, Stephen G. Andrews, Jaydira del Rivero, Jonathan M. Hernandez, Naris Nilubol, James P. Madigan, Samira M. Sadowski. Personalized therapeutic screening in patient derived organoids for gastroenteropancreatic neuroendocrine tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4234.