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Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors.

ABSTRACT: BACKGROUND & AIMS:In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling. METHODS:We obtained serum samples and gastric corpus biopsy specimens from 8 patients with hypergastrinemia and type 1 gNETs enrolled in a phase 2 trial of netazepide. Control samples were obtained from 10 patients without gastric cancer. We used amplified and biotinylated sense-strand DNA targets from total RNA and Affymetrix (Thermofisher Scientific, UK) Human Gene 2.0 ST microarrays to identify differentially expressed genes in stomach tissues from patients with type 1 gNETs before, during, and after netazepide treatment. Findings were validated in a human AGSGR gastric adenocarcinoma cell line that stably expresses human CCK2R, primary mouse gastroids, transgenic hypergastrinemic INS-GAS mice, and patient samples. RESULTS:Levels of pappalysin 2 (PAPPA2) messenger RNA were reduced significantly in gNET tissues from patients receiving netazepide therapy compared with tissues collected before therapy. PAPPA2 is a metalloproteinase that increases the bioavailability of insulin-like growth factor (IGF) by cleaving IGF binding proteins (IGFBPs). PAPPA2 expression was increased in the gastric corpus of patients with type 1 gNETs, and immunohistochemistry showed localization in the same vicinity as CCK2R-expressing enterochromaffin-like cells. Up-regulation of PAPPA2 also was found in the stomachs of INS-GAS mice. Gastrin increased PAPPA2 expression with time and in a dose-dependent manner in gastric AGSGR cells and mouse gastroids by activating CCK2R. Knockdown of PAPPA2 in AGSGR cells with small interfering RNAs significantly decreased their migratory response and tissue remodeling in response to gastrin. Gastrin altered the expression and cleavage of IGFBP3 and IGFBP5. CONCLUSIONS:In an analysis of human gNETS and mice, we found that gastrin up-regulates the expression of gastric PAPPA2. Increased PAPPA2 alters IGF bioavailability, cell migration, and tissue remodeling, which are involved in type 1 gNET development. These effects are inhibited by netazepide.

SUBMITTER: Lloyd KA

PROVIDER: S-EPMC7215182 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors.

Lloyd Katie A KA Parsons Bryony N BN Burkitt Michael D MD Moore Andrew R AR Papoutsopoulou Stamatia S Boyce Malcolm M Duckworth Carrie A CA Exarchou Klaire K Howes Nathan N Rainbow Lucille L Fang Yongxiang Y Oxvig Claus C Dodd Steven S Varro Andrea A Hall Neil N Pritchard D Mark DM

Cellular and molecular gastroenterology and hepatology 20200128 1

<h4>Background & aims</h4>In patients with autoimmune atrophic gastritis and achlorhydria, hypergastrinemia is associated with the development of type 1 gastric neuroendocrine tumors (gNETs). Twelve months of treatment with netazepide (YF476), an antagonist of the cholecystokinin B receptor (CCKBR or CCK2R), eradicated some type 1 gNETs in patients. We investigated the mechanisms by which netazepide induced gNET regression using gene expression profiling.<h4>Methods</h4>We obtained serum samples ...[more]

PMID: 32004755

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Project description:INTRODUCTION:Autoimmune chronic atrophic gastritis (CAG) causes hypochlorhydria and hypergastrinaemia, which can lead to enterochromaffin-like (ECL) cell hyperplasia and gastric neuroendocrine tumours (type 1 gastric NETs). Most behave indolently, but some larger tumours metastasise. Antrectomy, which removes the source of the hypergastrinaemia, usually causes tumour regression. Non-clinical and healthy-subject studies have shown that netazepide (YF476) is a potent, highly selective and orally-active gastrin/CCK-2 receptor antagonist. Also, it is effective in animal models of ECL-cell tumours induced by hypergastrinaemia. AIM:To assess the effect of netazepide on tumour biomarkers, number and size in patients with type I gastric NETs. METHODS:We studied 8 patients with multiple tumours and raised circulating gastrin and chromogranin A (CgA) concentrations in an open trial of oral netazepide for 12 weeks, with follow-up 12 weeks later. At 0, 6, 12 and 24 weeks, we carried out gastroscopy, counted and measured tumours, and took biopsies to assess abundances of several ECL-cell constituents. At 0, 3, 6, 9, 12 and 24 weeks, we measured circulating gastrin and CgA and assessed safety and tolerability. RESULTS:Netazepide was safe and well tolerated. Abundances of CgA (p<0.05), histidine decarboxylase (p<0.05) and matrix metalloproteinase-7(p<0.10) were reduced at 6 and 12 weeks, but were raised again at follow-up. Likewise, plasma CgA was reduced at 3 weeks (p<0.01), remained so until 12 weeks, but was raised again at follow-up. Tumours were fewer and the size of the largest one was smaller (p<0.05) at 12 weeks, and remained so at follow-up. Serum gastrin was unaffected. CONCLUSION:The reduction in abundances, plasma CgA, and tumour number and size by netazepide show that type 1 NETs are gastrin-dependent tumours. Failure of netazepide to increase serum gastrin further is consistent with achlorhydria. Netazepide is a potential new treatment for type 1 NETs. Longer, controlled trials are justified. TRIAL REGISTRATION:European Union EudraCT database 2007-002916-24 https://www.clinicaltrialsregister.eu/ctr-search/search?query=2007-002916-24ClinicalTrials.gov NCT01339169 http://clinicaltrials.gov/ct2/show/NCT01339169?term=yf476&rank=5.

Project description:Background and aimAbout a third of Pituitary Neuroendocrine Tumors (PitNETs) may show aggressive behavior. Many efforts have been performed for identifying possible predictive factors to early determine the future behavior of PitNETs. Programmed cell death ligand 1 (PD-L1) expression was associated with a more aggressive biology in different solid tumors, but its role in PitNET is not well-established yet. Our study aims to analyze PD-L1 expression in a surgical cohort of PitNETs to determine its association with radiological invasion and pathology findings, as well as with long-term recurrence rates.MethodsWe performed a retrospective analysis in a series of 86 PitNETs. Clinical presentation and radiological features of the preoperative period were collected, as well as pathological data and follow-up data. The rate of PD-L1 expression was immunohistochemically evaluated and expressed as a tumor proportion score (TPS). We assessed its relationship with cavernous sinus invasion and Trouillas' classification as primary outcomes. Secondary outcomes included the TPS' relationship with histopathological markers of proliferation, hormonal expression, tumor size and long-term recurrence rates. We calculated the optimal cut-point for the primary outcomes while maximizing the product of the sensitivity and specificity and then we evaluated the significance of secondary outcomes with logistic regression analysis.ResultsEighty-six patients were included in the analysis; 50 cases were non-functional PitNETs. The TPS for PD-L1 showed a highly right-skewed distribution in our sample, as 30.2% of patients scored 0. Using Trouillas' classification, we found that "proliferative" cases have a significantly higher probability to express PD-L1 in more than 30% of tumor cells (OR: 5.78; CI 95%: 1.80-18.4). This same cut-point was also associated with p53 expression. A positive association was found between PD-L1 expression and GH expression (p = 0.001; OR: 5.44; CI 95%: 1.98-14.98), while an inverse relationship was found with FSH/LH expression (p = 0.014; OR = 0.27, CI 95%: 0.10-0.76). No association was found with CS invasion, tumor size, bone erosion or dura invasion. We could not find any association between PD-L1 expression and recurrence.ConclusionsPD-L1 expression was associated with proliferative grades of Trouillas' classification and p53 expression. We also confirmed a higher expression of PD-L1 in somatotroph tumors. Larger studies are necessary to investigate the relationship between PD-L1 expression and aggressive behaviors.

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Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors.

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Netazepide Inhibits Expression of Pappalysin 2 in Type 1 Gastric Neuroendocrine Tumors.

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