Abstract A04: Identification of novel pancreatic cancer-specific biomarkers with organoid models

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is almost uniformly lethal and surgical intervention is the only cure. Unfortunately, the majority of patients are ineligible for resection because of the advanced stage of disease by the time of diagnosis. This is due in part to that lack of diagnostic tools, especially for families with elevated risk. Although considered an intractable and aggressive malignancy, progression from the initiating events to overt cancer requires approximately 12 years, and advancement to metastatic disease takes another 5 – 7 years. This latency indicates that there is a window for early detection and intervention. The PDA biomarker, CA19-9, is measured in the blood to follow tumor burden longitudinally, but is neither sensitive nor specific enough to be used for diagnosis. In particular, the use of CA19-9 in PDA diagnosis is problematic given the elevation of CA19-9 in benign conditions, such as pancreatitis, that have a higher incidence than PDA. To improve the diagnostic performance of CA19-9, we identified tissue- and cancer-specific protein carriers of the CA19-9 carbohydrate modification using murine and human organoid model systems of pancreatic cancer disease progression. To induce CA19-9 expression in murine organoids, two human gylcosyl transferases that were deficient in mice were ectopically expressed. CA19-9 protein carriers specific to malignancy were identified relative to normal, proliferating ductal cells. Some CA19-9 carriers that were shared between normal and malignant pancreatic ductal organoids were also detected in the sera of patients with benign pancreatic disease, highlighting their inability to distinguish malignancy from pancreatitis. Importantly, several of the tumor-specific novel CA19-9 carriers identified in organoids also discriminated between benign and malignant disease in human patient sera, and are nominated for clinical validation. Overall, organoid model systems allow identification of biomarkers that discriminate between normal proliferation and malignant conditions of multiple gastrointestinal tissues, providing a robust platform for biomarker discovery. Citation Format: Dannielle Engle, Herve Tiriac, Rivera Keith, Michael Ludwig, Chang-il Hwang, Kenneth Yu, Darryl Pappin, David Tuveson.{Authors}. Identification of novel pancreatic cancer-specific biomarkers with organoid models. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A04.