Abstract A061: Utility of patient-derived organoids for precision pharmacotyping, phenotypic screens, and modeling of pancreatic disease

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is projected to soon become the second leading cause of cancer death. Aberrant glycosylation is a hallmark of PDA, but the impact of glycosylation remains vastly understudied in PDA. Additionally, a lack of disease models that recapitulate glycosylation differences observed in human disease has hampered efforts to leverage glycan changes as therapeutic strategies. To address these needs, human patient-derived organoids (PDOs) were employed to address three major questions. First, the use of PDOs in drug screening experiments to characterize therapeutic sensitivity and resistance (i.e. “pharmacotyping”) is a promising precision medicine approach to inform clinical decisions. However, the extent to which different sources of basement membrane extracts (BMEs) in which PDOs are cultured contribute to organoid chemosensitivity profiles is unknown. Mouse and human PDA organoids representing a range of PDA disease stages (early, late, and metastasis) were subjected to a chemotherapy and targeted therapy pharmacotyping panel in different commercial BMEs. Differences in growth kinetics and drug response were analyzed. RNA-seq was performed to determine the impact of BME source on gene expression programs. Results from this work will provide key insights regarding optimal growth of pancreatic PDOs as well as the impact of exogenous factors on pharmacotyping results. Second, elevated serum levels of the glycan CA19-9 are observed in more than 75% of PDA patients. Recent evidence demonstrated that CA19-9 promotes pancreatitis and accelerates pancreatic tumorigenesis in mice, phenotypes that are reversible with the use of CA19-9-targeting antibodies. However, how CA19-9 synthesis is regulated is unknown. We developed organoid high-throughput screens to identify compounds that impact CA19-9 production. Continuing this screen across a library of hPDOs will lay the foundation for the identification of new therapeutic candidates and the understanding of regulators of glycosylation in PDA. Lastly, the pancreatitis is a major risk factor for the development of PDA, with hereditary pancreatitis patients having a 40-55% cumulative risk of developing PDA. However, reliable organoid models of human pancreatitis are lacking. To address this need, we optimized methods to derive PDOs from chronic pancreatitis specimens of genetic and non-genetic etiology. Human chronic pancreatitis organoids underwent multi-omic characterization and credentialing in order to provide the field with more representative models of pancreatitis in humans and a platform to explore early detection strategies and study pancreatic disease progression. Overall, we demonstrate the broad utility of PDOs to identify early detection biomarkers and targetable vulnerabilities in PDA. These models are a renewable resource for the field, enabling elucidation of the molecular underpinnings of the increased susceptibility of chronic pancreatitis to PDA and other fundamental aspects of PDA biology. Citation Format: Jan Lumibao, Shira Okhovat, Kristina Peck, Dannielle Engle. Utility of patient-derived organoids for precision pharmacotyping, phenotypic screens, and modeling of pancreatic disease [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A061.