Endocrine-related cancer · 2026
Effects of a GLP-1 agonist and anti-diabetic therapies on pheochromocytoma/paraganglioma growth.
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Wang Katharina, Stempfle Priska, Hamati Julia, Fischer Alessa, Maccio Umberto, Weber Achim, Robledo Mercedes, Maurer Julian, Peischer Lea, Reul Astrid, Kuzmenko Elena, Huber Alexander, Vetter Diana, Oberholzer Jose, Reisch Nicole, Zimmermann Petra, Knösel Thomas, Auer Matthias K, Lottspeich Christian, Beuschlein Felix, Hantel Constanze, Grossman Ashley B, Pacak Karel, Zitzmann Kathrin, Auernhammer Christoph J, Nölting Svenja
Аннотация
BACKGROUND: A high proportion of patients with pheochromocytomas and paragangliomas (PPGLs) show glycemic dysregulation. However, studies on the effects of anti-diabetic drugs on PPGL tumor growth are still lacking.
METHODS: We evaluated the effects of glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide, metformin and insulin on fresh patient-derived PPGL primary cultures (n=54), including 8 cluster 1 tumors and 18 cluster 2/3 tumors (n=4 tumors with RET pathogenic variants [PVs]). We correlated the primary culture data with clinical data from 67 patients enrolled in the prospective clinical trial PROSPHEO (NCT03344016).
RESULTS: We found cluster-dependent effects of semaglutide in patient primary cultures, with significant anti-tumor effects in cluster 1 PPGLs. Interestingly, we found tumor-promoting effects of high-dose semaglutide in 3 PPGLs with germline RET PVs (MEN2 syndrome), but not in a PPGL with a somatic RET PV. Metformin displayed overall anti-tumor effects while insulin showed individual tumor-promoting effects in the patient primary cultures. Consistently, clinical data confirmed larger median tumor sizes of PPGL patients receiving insulin therapy compared to patients receiving metformin/GLP-1RA therapy or patients without anti-diabetic therapy.
CONCLUSION: Overall, we provide novel data on the effects of anti-diabetic drugs on PPGL tumor growth including significant anti-tumor effects of the GLP-1RA semaglutide in cluster 1 PPGLs, and tumor-promoting effects in patients with MEN2 syndrome. Further confirmation of our data in prospective clinical studies is required.
METHODS: We evaluated the effects of glucagon-like peptide 1 receptor agonist (GLP-1RA) semaglutide, metformin and insulin on fresh patient-derived PPGL primary cultures (n=54), including 8 cluster 1 tumors and 18 cluster 2/3 tumors (n=4 tumors with RET pathogenic variants [PVs]). We correlated the primary culture data with clinical data from 67 patients enrolled in the prospective clinical trial PROSPHEO (NCT03344016).
RESULTS: We found cluster-dependent effects of semaglutide in patient primary cultures, with significant anti-tumor effects in cluster 1 PPGLs. Interestingly, we found tumor-promoting effects of high-dose semaglutide in 3 PPGLs with germline RET PVs (MEN2 syndrome), but not in a PPGL with a somatic RET PV. Metformin displayed overall anti-tumor effects while insulin showed individual tumor-promoting effects in the patient primary cultures. Consistently, clinical data confirmed larger median tumor sizes of PPGL patients receiving insulin therapy compared to patients receiving metformin/GLP-1RA therapy or patients without anti-diabetic therapy.
CONCLUSION: Overall, we provide novel data on the effects of anti-diabetic drugs on PPGL tumor growth including significant anti-tumor effects of the GLP-1RA semaglutide in cluster 1 PPGLs, and tumor-promoting effects in patients with MEN2 syndrome. Further confirmation of our data in prospective clinical studies is required.