Metabolomics-based Targeted Therapies for Gastric Cancer

Metabolic reprogramming is a hallmark of cancer and a promising target for developing new treatment. Prior to this project, we have shown that vagotomy suppressed tumorigenesis of gastric cancer (GC) (https://stm.sciencemag.org/content/6/250/250ra115.long). The aims of the present project were (i) to demonstrate that vagotomy-induced suppression of the tumorigenesis was associated with metabolic reprogramming and (ii) to develop metabolomics-based targeted therapy that inhibits the tumorigenesis and improves the overall survival. During the project period, we have performed a considerable number of laboratory studies (~50 experiments using 7 different cell lines and nearly 400 mice) and analyzed the "big data" including cells, animals and patient materials. First, we compared the transcriptomes of human and mouse GC and found that the the mice we used, i.e. the INS-GAS mice, were an excellent model of representing human GC. Based on the transcriptomics data, particularly the responses to vagotomy, we hypothesized that there was a “nerve-cancer metabolism axis”. Thus, we next employed metabolomics (including both liquid and gas chromatography) to analyze human vs mouse GC and mouse stomachs between wild-type and GC mice and between denervation and innervation, and constructed a “metabolic signature” in GC. Accordingly, we developed a new treatment regimen, namely combination of denervation and targeting signaling pathways with or without currently-used cytotoxic chemotherapies. Using in vitro model (human GC cells), we found potency and efficacy of various drugs per se and in different combinations of the drugs. According to the in vitro results, we further examined different treatment regimens using in vivo model (the INS-GAS mice) and followed up the animals for more than 2 years. We finally found that the best treatment regimen in terms of overall survival rate was in line with our hypothesis, namely targeting the nerve-cancer metabolism axis without cytotoxic drugs. Moreover, we performed RNAseq analysis of in vivo materials and confirmed the signaling pathways and nerve-cancer cell cross-talk underlying the new treatment. Importantly, we found that this metabolomics-based therapy was well tolerated at clinically relevant doses in aged mice with GC. Thus, we plan to translate it into clinical trials. To this end, we have first examined the stomachs of 17 GC patients and found that the metabolic signature of GC was correlated to 5-year survival rate and that malignant tissues displayed a distinct metabolic gene expression profile from adjacent tissue (metaplasia). This suggested a rational of treatment approach in which the local denervation to the tumor would be ideal. Next, we have tried it in a clinical trial (phase IIa in 6 patients) and found that the procedure is safe and feasible for future trial in a large number of patients. The results of this project has been published in iScience (www.cell.com/iscience/pdf/S2589-0042(21)00059-6.pdf). Gastric cancer is the 5th most common malignant disease worldwide with the 3rd highest incidence and mortality rate among all cancers. The 5-year overall survival rate for gastric cancer is 10-30%. It is also the 3rd highest cancer-related disability-adjusted life-years (DALYs) after lung and liver cancers. While H. pylori infection is declining, the trends towards increased obesity and aging of the population will likely result in a continued high incidence of gastric cancer. Thus, less invasive and better tolerated therapies need to be developed for the treatment of elderly patients with gastric cancer. Based on the successful progress in the treatment of gastric cancer in Japan over the last 50 years, it was suggested that endoscopic submucosal dissection (ESD) combined with “gentler” chemotherapy or immunotherapy could be applied to more than half of GC patients. The results of this project indicated that endoscopic submucosal/intratumoral injection of BoNT-A combined with non-cytotoxic chemotherapy could be an ideal therapy for the elderly patients. Of note is that the non-cytotoxic drugs, RAD001 (also known as everolimus) and CPI-613 (also known as devimistat) have been well tested in clinical trials for other types of cancer. In addition to gastric cancer, nerve-cancer crosstalk takes place in other types of cancer, e.g. prostate cancer, colorectal cancer, pancreatic cancer and breast cancer. This project may evoke more studies to investigate the underlying mechanisms, along with the metabolic reprogramming and immunometabolism, and to develop the nerve-cancer metabolism therapy for other cancer types.