Expression and Function of the Renin-Angiotensin System in the Esophagus
Condition: Barrett's Esophagus
MeSH terms: Barrett Esophagus
Study type: Interventional
Phase: Early Phase 1

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      components in BE with and without dysplasia (unpublished results).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, 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.
    

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.
    

Intervention name(s): Candesartan; Enalapril
Intervention type(s): Drug; Drug
Intervention description(s): Angiotensin II, type 1 receptor inhibitor, (candesartan) 8 mg once daily for; Angiotensin-converting enzyme (ACE) inhibitor (enalapril) 5 mg once daily
Other intervention name(s): Atacand, Ratacand, Biopress; CAS 139481-59-7, ATC C09CA06; Vasotec, Enaladex, Renitec; CAS 75847-73-3, ATC C09AA02
Intervention MeSH terms: Candesartan; Candesartan cilexetil; Enalapril
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Basic Science
Keywords: Gastrointestinal