Expression and Function of the Renin-Angiotensin System in the Esophagus

August 22, 2016 updated by: Göteborg University

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

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the investigators discovered the altered expression of "classical" RAS components in BE with and without dysplasia (unpublished results).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, in an exploratory prospective randomized placebo-controlled setting, whether RAS-related protein-expressions in BE are altered by the addition of RAS-suppressant pharmaceuticals. In the same manner the investigators wish to see if the expressions of well-known biomarkers for cancer and inflammation are altered.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

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 endocrine signalling system has been proven to utilise tissue-based character, being involved in pathological conditions such as inflammation, wound-healing and even cancer, in several organ systems.

The "classical" signalling pathway of RAS, when angiotensin II (AngII) is being formed by the help of angiotensin converting enzyme (ACE) and its affinity to the membrane-bound receptors (angiotensin II type 1 and 2 receptors (AT1R and AT2R)), is now being challenged by the discovery of "alternative" pathways with enzymes and receptors, making the picture more diverse.

Reports from the investigators laboratory indicate the existence of a local RAS in the esophageal wall musculature and in the squamous mucosa. This was further explored by Björkman et al 2013, showing that some RAS-components are significantly altered in patients with erosive reflux disease when compared to healthy volunteers. 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 investigators 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, in a exploratory prospective randomized placebo-controlled setting, whether RAS-related protein-expressions in BE are altered by the addition of RAS-suppressant pharmaceuticals. In the same manner the investigator wish to see if the expressions of well-known biomarkers for cancer and inflammation are altered.

Study Type

Interventional

Enrollment (Actual)

33

Phase

  • Early Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Sweden
      • Gothenburg, Sweden, S-41345
        • Dept. of Gastrosurgical Research and Education, Inst. Clinical Sciences, Sahlgrenska University Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Barretts esophagus with a minimum length of 1 cm and histomorphologically confirmed low grade dysplasia

Exclusion Criteria:

  • Treatment with ACE-inhibitors (angiotensin converting enzyme inhibitors) or AT1R-antagonists (angiotensin type 1 receptor antagonists). Newly diagnosed or treatment resistant hypertonia or renal failure.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: BASIC_SCIENCE
  • Allocation: RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: TRIPLE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
NO_INTERVENTION: no drug
No drug and no intervention
ACTIVE_COMPARATOR: AT1R-antagonist
Angiotensin II, type 1 receptor inhibitor, (candesartan) 8 mg once daily
Drug: Candesartan
Angiotensin II, type 1 receptor inhibitor, (candesartan) 8 mg once daily for
Other Names:
  • Atacand, Ratacand, Biopress; CAS 139481-59-7, ATC C09CA06
ACTIVE_COMPARATOR: ACE-inhibitor
Angiotensin converting enzyme inhibitor, (enalapril) 5 mg once daily
Drug: Enalapril
Angiotensin-converting enzyme (ACE) inhibitor (enalapril) 5 mg once daily
Other Names:
  • Vasotec, Enaladex, Renitec; CAS 75847-73-3, ATC C09AA02

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Assessed at baseline (day 0) and after three weeks (day 21) of treatment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Assessed at baseline (day 0) and after three weeks (day 21) of treatment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Göteborg University

Collaborators

Sahlgrenska University Hospital, Sweden

Investigators

  • Study Director: Anders F Edebo, MD PhD, Dept. of Gastrosurgical Research and Education, Inst. Clinical Sciences

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

October 1, 2009

Primary Completion (ACTUAL)

December 1, 2012

Study Completion (ACTUAL)

December 1, 2012

Study Registration Dates

First Submitted

May 31, 2016

First Submitted That Met QC Criteria

August 22, 2016

First Posted (ESTIMATE)

August 26, 2016

Study Record Updates

Last Update Posted (ESTIMATE)

August 26, 2016

Last Update Submitted That Met QC Criteria

August 22, 2016

Last Verified

August 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 233-09

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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