SUN-044 Sitagliptin for Treatment of Pituitary Adenomas Invading the Cavernous Sinus

Abstract Disclosure: E. Lefevre: None. F. Chasseloup: None. A. Dormoy: None. S. Deng: None. N. Ladurelle: None. C. Janot: None. M. Hage: None. M. Hage: None. K. Chappel: None. A. Larabi: None. J. Alvarez: None. P. Zizzari: None. J. Bouligand: None. J. Young: None. P. Chanson: None. S. Viengchareun: None. M. Buchfelder: None. P. Kamenicky: None. Context: Cavernous sinus invasion by pituitary adenomas remains challenging in clinical practice. In this study we aimed to identify the molecular actors involved their invasive phenotype and test novel therapeutic approaches. Methods: Using RNA-seq, we compared the gene expression profiles of human intrasellar non-invasive portions and intracavernous invasive portions of the same pituitary adenoma samples. Among the up-regulated genes in the invasive portions, we selected those involved in tumorigenesis and invasiveness that exhibited consistent overexpression in the intracavernous samples. In vitro functional studies of selected genes were performed in murine lactostomatotroph GH3 cells and gonadotroph LbT2 cells using the Transwell Assay. Further, in vivo experiments were conducted using an original orthotopic model of invasive somatotroph pituitary tumors generated via stereotaxic GC cell injection into the pituitary lobes of immunocompetent rats. After surgery, rats were monitored weekly, and tumor progression was assessed fortnightly by 3 successive 7 Tesla MRIs. Half of the rats received experimental treatment. Treatment’s efficacy was evaluated by tumor progression and survival outcomes. Results: RNA-seq of 52 samples from 26 patients with somatotroph or gonadotroph invasive pituitary adenomas identified 32 upregulated genes in the invasive portions of the adenomas. Among these, di-peptydyl-peptidase-4 (DPP4) was homogeneously upregulated in 21 out of 26 (81%) invasive portions and is known for its role in extracellular matrix degradation in cancer, warranting further investigations. In vitro, pharmacological inhibition of the DPP4 with sitagliptin reduced cell migration and invasion in GH3 cells (p=0.0205 and p=0.0038) and LbT2 cells (p=0.0345 and p=0.0131) in Transwell assays. In vivo, 24 out of 28 injected rats (86%) developed invasive pituitary tumors. Tumor growth was rapid, leading to obstructive hydrocephalus-related death in 92.3 % of control animals versus 63.6% of animals receiving sitagliptin by day 49. Sitagliptin treatment increased overall survival (p = 0.0389) and slowed tumor growth, as shown by volumetric 7 Tesla MRI studies (tumor volume = 45.4 vs 131.2 mm3 on day 28; p = 0.036). In conclusion, we identified DPP4 as a key molecular driver promoting the invasive behavior of pituitary adenomas. Pharmacologic inhibition of DPP4 with sitagliptin, that has been largely used for treatment of diabetes, could be a promising therapeutic approach in invasive pituitary tumors. Presentation: Sunday, July 13, 2025