Abstract A059: Serum EphA2 proteolytic fragment is a potent biomarker for diagnosing a very early stage of ductal pancreatic carcinoma

Abstract Erythropoietin-producing hepatocellular receptor A2 (EphA2) is a receptor tyrosine kinase, and its expression increases with malignant progression of cancer. Therefore, EphA2 is believed to be a candidate for molecular cancer therapy and many candidate drugs targeting EphA2 have been developed, but their effects are limited. The reason is its complex signaling functions. In fact, EphA2 has a tumor suppressor function regulated by the stimulation of the Ephrin-A ligand, while in the absence of ligand stimulation, it has a prooncogenic function in collaboration with EGFR and its downstream signaling molecules. The opposite functions of EphA2 make it difficult to develop it as a cancer drug target. We have previously demonstrated that a type-1 matrix membrane metalloprotease (MT1-MMP) at cancer cell surface interacted with EphA2 and selectively cleaved its N-terminal ligand binding site, converting it into a prooncogenic signaling transmitter (Koshikawa N et al., Cancer Research, 2015). We also found that the N- terminal fragment of EphA2 (termed EphA2-NF) released by MT1-MMP cleavage increased in sera from patients with gastric cancer and ductal pancreatic carcinoma (PDC) (Koshikawa N et al., Cell Death & Disease, 2017). In this study, we compare the expression of EphA2-NF in serum from a healthy donor (HD: 150 cases), patients with chronic pancreatic disease (87 cases), and PDC (578 cases) by automated chemiluminescence immunoassay with a specific EphA2-NF monoclonal antibody. As a result, PDC cases, including stage I/II PDC, show significantly higher levels of EphA2-NF than HD (Sato et al. Cancer Research Communications, 2023). Furthermore, PDC occurred in the intraductal papillary mucinous neoplasm (IPMN) cases with high levels of EphA2-NF during follow-up observation. Therefore, to verify that the EphA2 proteolytic cleavage occurred in the PDC onset, we analyzed 50 surgical resected tissues from patients with PDC and IPMN to detect the N and C-terminal regions of EphA2 by immunohistochemical staining. Interestingly, PDC, including early stage PDC cases, lacked the N-terminus of EphA2. Furthermore, the deletion of N-terminus of EphA2 was observed in all tested cases pathologically diagnosed as intraductal papillary mucinous adenocarcinoma (IPMC) (Sato S et al., Cancer Research Communications, 2023). These results suggest that serum EphA2-NF has the potential to revolutionize the early detection and management of PDC, providing a valuable tool to diagnose the disease in very early stages when treatment results may be more favorable. Collaborators: Masatoshi Nakagawa, Eisaku Yoshida and Toru Yoshimura (Research and Development, Abbott Japan LLC) Citation Format: Naohiko Koshikawa, Shinya Sato, Kouki Nio, Takeshi Terashima, Makoto Ueno, Taro Yamashita. Serum EphA2 proteolytic fragment is a potent biomarker for diagnosing a very early stage of ductal pancreatic carcinoma [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr A059.