Metabolomics-based Targeted Therapies for Gastric Cancer
A New Regimen for Treatment of Gastric Cancer: Targeting Glutamine-Dependent Wnt/beta-Catenin-mTOR Signaling
Metabolomics has made considerable technical advances in recent years. In this project, we have taken these advances to timely translate the knowledge to the field of patient-oriented cancer research. Based on cell culture studies, aniaml experiments and analyses of patients' tissue samples, we have developed a new regimen to treat gastric cancer.
Main results: Paper I: In this study, we ought to develop a new regimen to target the nerve-mediated glutamine-dependent WNT/b-catenin-mTOR signaling and cell proliferation. In patients, neurotrophin signaling, axonal guidance pathway, WNT signaling and L-glutamate pathways were upregulated in cancer vs. adjacent non-cancerous tissues. In INS-GAS mice, denervation inhibited the glutaminolytic pathway, including reductions in glutamine, glutamate and glycine. It also inhibited the mTOR pathway. Cancer cells in culture were highly dependent on glutamine and glucose. Screening of agents for growth inhibitory effect revealed the following order of potency: Caelyx>RAD001>Oxaliplatin/Cisplatin>CPI-613>5-FU>Botox. Reduced glutamine concentration increased Cisplatin IC50 by 2-3 folds. INS-GAS mice were treated with Botox by gastric injections along with various combinations of the drugs by i.p. injection for 2 months. Tumor size was significantly reduced by combination therapies. Thus, targeting the glutamine-dependent WNT/beta catenin-mTOR pathway in combination with chemotherapy represents a promising new therapeutic strategy for gastric cancer. This was presented in Digestive Disease Week 2016 and the abstract was published in Gastroenterology. Full manuscript is in preparation for publication. Paper II: In this study, we have utilized approaches of metabolomics and transcriptomics to specifically analyze the metaplasia in comparisons with cancer and non-cancer tissues in the same patients. 17 patients with gastric adenocarcinoma were studied. Comparison between metaplasia and non-cancer tissues revealed the following upregulated metabolic pathways: GalNAcbeta1-3Gal pathway, histidine-glutamate-glutamine and proline metabolism. In the stomach diseases, top genes and pathways included XRN2, Noxin (a stress-induced gene), NOTCH1, NOTCH2, NOTCH3, COX-2, HIWI, ionotropic glutamate receptor, and microRNA 223, and Cytoskeleton remodeling_TGF, WNT and cytoskeletal remodeling and Development_Regulation of EMT. This was presented at Digestive Disease Week 2016 and published in Gastroenterology 2016. Full manuscript is in preparation for publication. Paper III: In this study, we wanted to develop a new treatment with ITCs for gastric cancer. Treatment of gastric cancer cells lines AGS, MKN45, MKN74 and Kato-III with PEITC and Cisplatin separately resulted in time- and dose-dependent inhibition on growth. Pretreatment with PEITC displayed time-and dose-dependent synergistic effects when combined with Cisplatin. Furthermore, PEITC depleted glutathione by 66% and 91% after only 3 h of treatment. PEITC also induced p53 protein level, disrupted microtubular filaments and increased caspase-3 activity. Thus, PEITC acted as a multi-target anticarcinogen with potential in gastric chemoprevention and adjuvant chemotherapy. The results were presented as in DDW 2016 and abstract was published in Gastroenterology 2016. Full manuscript is in preparation for publication. Paper IV: Review article: “Vagotomy and Gastric Tumorigenesis” published, Curr Neuropharmacol 2016;14(8):967-972 International conferences: • 2016-05-20-24: Digestive Disease Week, San Diego with one poster and one oral presentations • 2016-06-16-17: 1st international NTNU symposium on current and future clinical biomarkers of cancer, NTNU • 2016-06-20-23: 2016 Workshop on Translational Medicine: National University of Singapore (NUS) and NTNU
A Potential New Regimen for Treatment of Gastric Cancer: Targeting Glutamine-dependent WNT/ß-catenin-mTOR Signaling
Several different kinds of drugs were tested either alone or in combination in four human gastric cancer cell lines and the mouse model of gastric cancer."Tricyclie" regimen was found to be the most effective, namely local Botox injection into the tumor with systemic administrations of RAD001/CPI-613 and 5-FU, platinum-drugs and/or Caelyx.
Background/aim: Previously, we showed that the WNT/ß-catenin signaling pathway was upregulated in gastric cancer of humans and mouse models and that denervation by either vagotomy or botulinum toxin type A (Botox) injection suppresses gastric tumorigenesis through inhibition of WNT/ß-catenin signaling pathway in mice. In the present study, we sought to develop a new regimen to target the nerve-mediated glutamine-dependent WNT/ß-catenin-mTOR signaling and the cell proliferation. Methods: Thirty-four patients with gastric adenocarcinoma and 139 INS-GAS mice, a genetic mouse model of spontaneous gastric cancer, were included. Gene expression profiling and metabolic profiling in the stomachs were performed using Illumina arrays, GeneGo pathway analysis, and Metabolome analysis. Human gastric cancer cell lines, AGS, KATO III, MKN 45 and MKN 74, were used. The drugs used included: Botox® (cleavage of the SNARE substrate SNAP25), RAD001 (mTOR inhibitor), CPI613 (targeting pyruvate dehydrogenase), 5-fluorouracil (5-FU), platinum-based agents including cisplatin and oxaliplatin, and liposomal doxorubicin (Caelyx, nucleosome destabilization). Results: In patients, neurotrophin signaling, axonal guidance pathway, WNT signaling, L-glutamate pathways and transport were upregulated in cancer vs. adjacent non-cancerous tissues. In INS-GAS mice, denervation inhibited the glutaminolytic pathway, which included reductions in glutamine, glutamate and glycine. It also inhibited the mTOR pathway. Cancer cells in culture were highly dependent on both glutamine and pyruvate. Screening of agents for growth inhibitory effect revealed the following order of potency: Caelyx > RAD001 > CPI613 > oxaliplatin/cisplatin > 5-FU > Botox. Combination of these agents at IC10-50 resulted in either additive or synergistic effects of > 90% growth inhibition. Reduced glutamine concentration increased cisplatin IC50 by 2-3 folds. INS-GAS mice developed advanced gastric cancer at 10-12 months of age, and were then treated with Botox by gastric injections (once a month) along with various combinations of the drugs (see above) given by i.p. injection for 2 months. Tumor size was significantly reduced by combination therapies, i.e. Botox + RAD001 (67% efficacy), Botox + RAD001 + 5-FU + oxaliplatin (67%), Botox + CPI613 (67%), Botox + CPI613 + 5-FU + oxaliplatin (71%), and Botox + Caelyx + 5-FU + oxaliplatin (80%) compared with chemotherapy only. Importantly, the survival rate was significantly increased in mice treated with Botox + RAD001+ CPI613 + 5-FU + oxaliplatin. Conclusions: Targeting the glutamine-dependent WNT/ß-catenin-mTOR pathway in combination with chemotherapy represents a promising new therapeutic strategy for gastric cancer. We propose “Tricyclie” regimen as local Botox injection with systemic administrations of RAD001/CPI-613 and 5-FU, platinum-drugs and/or Caelyx.
Steady-state energy balance in animal models of obesity and weight loss.
Scand J Gastroenterol 2016 Dec 20. Epub 2016 des 20
Vagotomy and Gastric Tumorigenesis.
Curr Neuropharmacol 2016;14(8):967-972.
PYY-Dependent Restoration of Impaired Insulin and Glucagon Secretion in Type 2 Diabetes following Roux-En-Y Gastric Bypass Surgery.
Cell Rep 2016 May 03;15(5):944-50. Epub 2016 apr 21
Signet ring cell carcinomas identified as a molecular subtype of gastric cancer.
Gastroenterology.2016: Volum150, (4,) Suppl 1, S80
A New Regimen (“Tricyclie”) for Treatment of Gastric Cancer: Targeting Glutamine-Dependent Wnt/ß-Catenin-mTOR Signaling
Gastroenterology 2016 ;Volum 150.(4) Suppl. 1 s. 866-866
Intragastric Injection of Botulinum Toxin a to Treat Obesity: Mechanism and Phase II Trial Study.
Gastroenterology 2016 ;Volum 150.(4) Suppl. 1 s. 823-823
Fant hormon som kan bli medisin mot diabetes.
gemini.no [Internett] 2016-05-15
Nytt norsk funn kan ta knekken på diabetes.
tv2.no [Internett] 2016-05-15
Vagal blocking for obesity control: a possible mechanism-of-action
Obesity Surgery 2016 ;Volum Published ahead of print. s. 1-9
NTNU-forskere fant hormon som kan ta knekken på diabetes.
abcnyheter.no [Internett] 2016-05-16
Roux-En-Y Gastric Bypass Surgery Restores Impaired Islet Architecture and Function in Type-2 Diabetes by PYY.
Gastroenterology 2016 ;Volum 150.(4) Suppl. 1 s. 116-116
Possible mechanism of naturally occurring isothiocyanates in chemoprevention and adjuvant chemotherapy for gastric cancer.
Gastroenterology 2016 ;Volum 150.(4) Suppl. 1 s. 116-116