Abstract 4000: The significance of GLP-1R and its agonist in neuroendocrine neoplasms

Abstract Neuroendocrine neoplasms (NENs) are rare cancers originating from neuroendocrine cells that are found throughout the body. NENs are subdivided into 2 categories: Well-differentiated neuroendocrine tumors (NET) and poorly differentiated neuroendocrine carcinomas (NEC). Both NET and NEC are highly metastatic and difficult to treat. NEN cases are on the rise and yet the etiology remains unclear. Commonly used drugs such as proton pump inhibitors can promote NET growth and result in poor prognosis for NET patients. Nowadays, the diabetes and weight loss drug semaglutide, a glucagon-like peptide 1 receptor (GLP-1R) agonist, has gain extensive popularity and are currently being taken by over 15 million people in the USA. Semaglutide is contraindicated for NET patients with medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome type 2 (MEN2) since some of these cancers express the GLP-1R. However, this area of research remains understudied. Little is known about the expression levels of GLP-1R in NEN from different anatomical locations and their response to semaglutide since these are rare cancers and few NET models are available for drug testing. We recently identified 2 human NET cell lines (GOT1 and NT-3) that express the GLP-1R and showed that semaglutide promotes tumor cell growth both in vitro and in vivo. In this study, we aim to investigate the levels of GLP-1R expression in a large collection of NEN tissue microarrays and determine the effects of semaglutide in novel GLP-1R positive NET patient-derived spheroid cultures. We stained for GLP-1R expression by immunohistochemistry in 357 NET tissue microarrays covering 7 classes of NEN: 78 pancreas NET, 62 duodenum NET, 33 ileal NET, 42 lung NET, 10 small cell lung NEC, 12 extrapulmonary visceral NEC, 29 thyroid NET, 12 gastric NET, 6 appendix NET, 6 rectum NET, 22 pheochromocytoma, 22 paraganglioma, and 23 Merkel cell carcinoma. Furthermore, we generated GLP-1R positive pancreas, ileal, and duodenal NET spheroids for drug testing. Our data showed 45% of duodenum NET, 17% of gastric NET, and 14% of pancreas NET stained positive for GLP-1R expression. Less than 2% of other classes NET or NEC stained positive for GLP-1R expression. Using newly established NET patient-derived spheroid models, we demonstrated that 100 nM of semaglutide accelerates tumor cell growth by 1.4 to 2-fold. Surprisingly, duodenum NET is the class of NET that frequently express GLP-1R and should be highly cautioned for the semaglutide usage. Citation Format: Sophia A. Hueser, Reese E. Townsend, Casandro J. Chan, Leona Rupp, Leopaul J. Chan, Dawn E. Quelle, Joseph S. Dillon, Andrew M. Bellizzi, James R. Howe, Po Hien H. Ear. The significance of GLP-1R and its agonist in neuroendocrine neoplasms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4000.