Project 3: GLP1R and GIPR Agonists in GEP NETs Project

University Of Iowa, Iowa City IA

Investigators

Abstract

Project 3 – Summary Incretin mimetics that activate the glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors are increasingly prescribed in the U.S. for diabetes and obesity. These drugs include the GLP-1 receptor (GLP-1R) agonist, semaglutide, and the dual GLP-1/GIP receptor (GLP-1R/GIPR) agonist, tirzepatide. Gastroenteropancreatic (GEP) neuroendocrine tumors (NETs), one of the most prevalent types of GI tumors, commonly express GLP-1R and/or GIPR. While GIPR expression appears largely ubiquitous across GEPNETs, GLP-1R expression is more variable. Our pilot studies revealed that treatment of receptor-positive GEPNET cell lines and patient-derived spheroids with these receptor activating agents caused increased cell growth in vitro and xenograft tumor growth in vivo. With the rising use of these diabetes and obesity drugs, high receptor levels on many GEPNETs, and delayed diagnosis of GEPNETs, it is possible that these drugs will accelerate GEPNET growth leading to more advanced presentation at diagnosis. Thus, it is critical to study how the different incretin mimetics affect GEPNET biology and progression. The central hypothesis of this project is that GLP-1R and GIPR agonists selectively promote GEPNET growth depending on expression levels of their targeted receptors. • Aim 1. Define the specificity of GLP-1R vs GIPR expression in patient GEPNETs and associations with clinicopathologic variables • Aim 2. Establish the biological impact and receptor dependence of GLP-1R and GIPR agonists in GEPNET models. • Aim 3. Determine the impact of approved NET therapies, somatostatin analogues (SSAs) and everolimus, on the effects of GLP-1R and GIPR agonists in GEPNETs The exploding use of GLP-1R and/or GIPR incretin mimetics for obesity and diabetes may lead to unwanted proliferation of cells expressing high levels of their receptors, which includes many NETs. Patients with occult NETs who take these GLP-1R and/or GIPR agonists may therefore be at risk of developing more rapidly progressive disease. Understanding the receptor dependence and mechanisms by which incretin mimetics promote NET proliferation, as well as determining which patients are at highest risk, will inform how these drugs may be used safely by NET patients. Specifically, our data suggest that GLP-1R specific agonists (semaglutide) could be safe for patients whose NETs lack that receptor, whereas GIPR agonists (tirzepatide) may have tumor promoting effects on most, if not all, GEPNETs due to widespread GIPR expression. This project will define whether and how incretins can be given safely to NET patients. Our team is uniquely equipped to address those questions, which have high clinical relevance and are in urgent need of answers.