Correction: Netazepide, a Gastrin Receptor Antagonist, Normalises Tumour Biomarkers and Causes Regression of Type 1 Gastric Neuroendocrine Tumours in a Nonrandomised Trial of Patients with Chronic Atrophic Gastritis

Abstract

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 followup. 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.

Gastric Corpus Mucosal Hyperplasia and Neuroendocrine Cell Hyperplasia, but not Spasmolytic Polypeptide-Expressing Metaplasia, Is Prevented by a Gastrin Receptor Antagonist in H+/K+ATPase Beta Subunit Knockout Mice

“…Similarly, carcinogenesis in M. natalensis is enhanced by the histamine 2 receptor antagonist (H2RA) loxtidine [30], but inhibited by NTZ [31] and likewise gastric carcinogenesis in hypergastrinemic transgenic INS-GAS mice is inhibited by NTZ [32]. In patients with hypergastrinemia due to chronic atrophic gastritis, we have reported that NTZ can eradicate (type 1) ECL cell NE tumors (NETs) [33][34][35]. Interestingly, patients with chronic atrophic gastritis have an increased risk of both gastric adenocarcinomas and NETs [36][37][38].…”

Do Gastric Signet Ring Cell Carcinomas and ECL-Cell Neuroendocrine Tumours Have a Common Origin?

“…The proliferation of enterochromaffin-like (ECL) cells of the gastric corpus and fundus is stimulated by gastrin and most gastric neuroendocrine tumours (NETs) develop due to long-term hypergastrinemia. Gastric NETs develop in patients with autoimmune chronic atrophic gastritis (CAG) (type 1), as well as in patients with gastrinomas (type 2), and type 1 gastric NETs regress after treatment with a gastrin receptor antagonist [1,2]. The main risk factor for gastric adenocarcinomas is Helicobacter pylori infection with extensive atrophic gastritis [3] that leads to gastric hypoacidity.…”