Metabolomics-based Targeted Therapies for Gastric Cancer
Metabolomics-based Targeted Therapies for Gastric cancer
During this first year of the PhD project, we have performed a series of cell culture and animal experiments to test 26 different treatment regimens for gastric cancer. We have collected biological sampels and are performing analyses. In addition, I have published a review article and given 3 presentations in international conferences/symposia.
Goals for the first year (2016): 1) Complete PhD coursework 2) Conduct cell culture and animal testing of targeted treatments for validation of metabolic targets as a translational study to novel clinical trials (i.e. combination of chemotherapy and multiple-targeted therapy). Results: 1) Completed PhD coursework (30 credits) 2) Preliminary results: - A Potential New Regimen ("Tricyclie") for Treatment of Gastric Cancer: Targeting Glutamine-Dependent Wnt/b-Catenin-mTOR Signaling In the present 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. Targeting the glutamine-dependent WNT/b catenin-mTOR pathway in combination with chemotherapy represents a promising new therapeutic strategy for gastric cancer. This was presented in Digestive Disease Week (DDW), San Diego, 2016-05-20-24 and the abstract was published in Gastroenterology, 150(4):S866, 2016. Full manuscript is in preparation. - Possible Mechanism-of-Action of Naturally Occurring Isothiocyanates in Chemoprevention and Adjuvant Chemotherapy for Gastric Cancer In this study, we wanted to demonstrate the potential of ITCs in chemoprevention and adjuvant chemotherapy in gastric cancer and determine underlying mechanism of action. Treatment of gastric cancer cells lines AGS, MKN45, MKN74 and Kato-III with PEITC (1-100 µM) and Cisplatin (5-200 µM) separately resulted in time- and dose-dependent inhibition on growth. Pretreatment with PEITC at 10 and 20 µM displayed time-and dose-dependent synergistic effects when combined with Cisplatin. Furthermore, PEITC depleted glutathione by 66% (10 µM) and 91% (20 µM) after only 3 h of treatment. PEITC also induced p53 protein level, disrupted microtubular filaments and increased caspase-3 activity. In conclusions: PEITC acted as a multi-target anticarcinogen with potential in gastric chemoprevention and adjuvant chemotherapy. The results was presented as in DDW, San Diego, 2016-05-20-24 and abstract was published in Gastroenterology, 150(4):S110, 2016. Full manuscript is in preparation. 3) Review article: “Vagotomy and Gastric Tumorigenesis” published, Curr Neuropharmacol 2016;14(8):967-972, PMID: 26791481 4) Conferences/Meetings: • 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
Vagotomy and Gastric Tumorigenesis.
Curr Neuropharmacol 2016;14(8):967-972.
PMID: 26791481 - Inngår i doktorgradsavhandlingen
Intragastric Injection of Botulinum Toxin A to Treat Gastric Cancer: An Open-Label Phase II Clinical Trial
Gastroenterology, 150(4):S1251-S1252, 2016
A Potential New Regimen (“TRiCyClE”) for Treatment of Gastric Cancer: Targeting Glutamine-dependent WNT/ß-catenin-mTOR Signaling
Gastroenterology 150(4):S866, 2016
Possible mechanism-of-action of isothiocyanates in chemoprevention and adjuvant chemotherapy for gastric cancer
Gastroenterology 150(4):S110, 2016.