Clinical Trial: Expression and Function of the Renin-Angiotensin System in the Esophagus

Study Status: Completed
Recruit Status: Completed
Study Type: Interventional

Official Title: The Renin-angiotensin System (RAS) in Barrett's Esophagus as Future Biomarkers for Dysplasia and Cancer? A Randomized Controlled Trial

Brief Summary:

Barrett`s esophagus (BE) is the major esophageal pre-neoplastic lesion in which dysplastic transformations eventually can lead to cancer development. Today, the only way for early detection of pre-neoplastic lesions is an endoscopic surveillance programme with tissue sampling for histopathology, the latter being the only validated biomarker for esophageal adenocarcinoma (EAC)-risk available. New biomarkers are warranted for better patient selection before inclusion into BE surveillance programmes.

Epidemiologic studies have demonstrated suppressed numbers of cancer prevalence in cohorts being under different medical treatment. In a British epidemiological study 2007 Sjöberg et al noted a lower prevalence of EAC among patients treated with antihypertensive drugs interfering with the renin-angiotensin system (RAS) such as AT1R-blockers and ACE-inhibitors. The last decade this endocrine signalling system has been proven to be involved in pathological conditions such as inflammation, wound-healing and even cancer, in several organ systems.

Earlier reports from the investigators laboratory indicate the existence of a local RAS in the esophageal wall musculature and in the squamous mucosa. In the investigators latest explorative study, the investigators discovered the altered expression of "classical" RAS components in BE with and without dysplasia (unpublished results).

By a possible alteration in RAS-related protein-expression in BE with increasing grade of dysplasia towards EAC, the investigator may have a possible "pathway" leading to biomarkers for cancer-development. Furthermore, the already well-known anti-hypertensive drugs ACE-inhibitors and AT1R-blockers may interfere with the risk of malignancy in BE. The investigators therefore wish to test, i

Detailed Summary:

Barrett`s esophagus (BE) is the major esophageal pre-neoplastic lesion in which dysplastic transformations eventually can lead to cancer development. Early detection of high-grade dysplasia (HGD) or intramucosal cancer is of fundamental value for the patient. The minimally invasive endoscopic resection- and ablation-techniques available are curative. In patients with invasive cancer far more invasive resection-techniques are required which are associated with severe post-operative morbidity, mortality and poor overall survival. Today, the only way for early detection of pre-neoplastic lesions is an endoscopic surveillance programme with tissue sampling for histopathology, the latter being the only validated biomarker for esophageal adenocarcinoma (EAC)-risk available. In an unselected BE-population the risk of developing EAC is low, 0.12% annually. In patients with BE and low-grade dysplasia (LGD) the number of EAC is 5,1 per 1000 person-years according to a large Danish cohort-study. New biomarkers are warranted for better patient selection before inclusion into BE surveillance programmes.

Epidemiologic studies have demonstrated suppressed numbers of cancer prevalence in cohorts being under different medical treatment. Anti-inflammatory, lipid-lowering and anti-hypertensive drugs are mentioned. In a British epidemiological study 2007 Sjöberg et al noted a lower prevalence of EAC among patients treated with antihypertensive drugs interfering with the renin-angiotensin system (RAS) such as AT1R-blockers and ACE-inhibitors. Wegman-Ostrosky et al linked RAS to the "Hallmarks of cancer" by RAS directly affecting tumor and stromal cells, and indirectly by affecting vascular cells in angiogenesis.

RAS is known to be involved in fluid and electrolyte homeostasis and in hemodynamic regulation. The last decade this e
Sponsor: Göteborg University

Current Primary Outcome: Change in expression of proteins associated with inflammation, proliferation and cancer development [ Time Frame: Assessed at baseline (day 0) and after three weeks (day 21) of treatment ]

Change in expression of p53, AMACR, Caspase 3, iNOS, VEGFR2, EGFR, CyclinD1, NFkB, PPARy, Cox-2, NLRP3 and MPO after 3 weeks treatment, assessed by Western blot.


Original Primary Outcome: Same as current

Current Secondary Outcome: Change in regulation of potential new biomarkers associated with esophageal cancer [ Time Frame: Assessed at baseline (day 0) and after three weeks (day 21) of treatment ]

Change in regulation after 3 weeks treatment of proteins associated with esophageal cancer assessed by global proteomic analysis. Expression of regulated proteins found in the proteomic analysis are further investigated with Western blot.


Original Secondary Outcome: Same as current

Information By: Göteborg University

Dates:
Date Received: May 31, 2016
Date Started: October 2009
Date Completion:
Last Updated: August 22, 2016
Last Verified: August 2016