Vagotomy reduces gastric acid secretion and was therefore introduced as a surgical treatment for peptic ulcers in the 1970s. Later, it was replaced by acid reducing medication, such as histamine type 2 (H2) receptor antagonists and proton pump inhibitors (PPIs). A large body of evidence has indicated that drug-induced hypochlorhydria per se does not increase the risk of gastric cancer. Early studies on the effects of vagotomy in chemically-induced rodent models of gastric cancer reported an increased risk of developing gastric cancer. This was most likely due to a delayed gastric emptying, which later has been accounted for by including an additional drainage procedure, e.g. pyloroplasty. In a recent study using three different mouse models of gastric cancer (including genetically engineered, chemically-induced and Helicobacter pylori-infected mice), either unilateral vagotomy or bilateral truncal vagotomy with pyloroplasty was found to significantly attenuate tumorigenesis in the denervated side of the stomach at early preneoplastic stages as well as at later stages of tumorigenesis. Consistently, pharmacological denervation using botulinum toxin A or muscarinic acetylcholine receptor 3 (M3R) blockade inhibited tumorigenesis. Moreover, it was found that recurrence of gastric cancer was reduced in patients following vagotomy. Thus, these new findings suggest the potential treatment strategies to target the nerve, neurotransmitters, corresponding receptors and their downstream signaling pathways for the malignancy.

Tumors comprise cancer cells and the associated stromal and immune/inflammatory cells, i.e., tumor microenvironment (TME). Here, we identify a metabolic signature of human and mouse model of gastric cancer and show that vagotomy in the mouse model reverses the metabolic reprogramming, reflected by metabolic switch from glutaminolysis to OXPHOS/glycolysis and normalization of the energy metabolism in cancer cells and TME. We next identify and validate SNAP25, mTOR, PDP1/a-KGDH, and glutaminolysis as drug targets and accordingly propose a therapeutic strategy to target the nerve-cancer metabolism. We demonstrate the efficacy of nerve-cancer metabolism therapy by intratumoral injection of BoNT-A (SNAP25 inhibitor) with systemic administration of RAD001 and CPI-613 but not cytotoxic drugs on overall survival in mice and show the feasibility in patients. These findings point to the importance of neural signaling in modulating the tumor metabolism and provide a rational basis for clinical translation of the potential strategy for gastric cancer.

Objective: The aim of the present study was repositioning of ivermectin in treatment of gastric cancer (GC) by computational prediction based on gene expression profiles of human and mouse model of GC and validations with in silico, in vitro and in vivo approaches.Methods: Computational drug repositioning was performed using connectivity map (cMap) and data/pathway mining with the Ingenuity Knowledge Base. Tissue samples of GC were collected from 16 patients and 57 mice for gene expression profiling. Additional seven independent datasets of gene expression of human GC from the TCGA database were used for validation. In silico testing was performed by constructing interaction networks of ivermectin and the downstream effects in targeted signaling pathways. In vitro testing was carried out in human GC cell lines (MKN74 and KATO-III). In vivo testing was performed in a transgenic mouse model of GC (INS-GAS mice).Results: GC gene expression “signature” and data/pathway mining but not cMAP revealed nine molecular targets of ivermectin in both human and mouse GC associated with WNT/β-catenin signaling as well as cell proliferation pathways. In silico inhibition of the targets of ivermectin and concomitant activation of ivermectin led to the inhibition of WNT/β-catenin signaling pathway in “dose-depended” manner. In vitro, ivermectin inhibited cell proliferation in time- and concentration-depended manners, and cells were arrested in the G1 phase at IC50 and shifted to S phase arrest at >IC50. In vivo, ivermectin reduced the tumor size which was associated with inactivation of WNT/β-catenin signaling and cell proliferation pathways and activation of cell death signaling pathways.Conclusion: Ivermectin could be recognized as a repositioning candidate in treatment of gastric cancer.