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Gene Expression And DNA Methylation In Barrett's Oesophagus And Oesophageal Adenocarcinoma
Funder
National Health and Medical Research Council
Funding Amount
$383,655.00
Summary
The oesophagus (gullet) is the tube through which food and drinks pass from the mouth to the stomach. In Barrett's oesophagus, the normal lining of the lower oesophagus is replaced by an abnormal type of lining called intestinal metaplasia as a result of severe gastroesophageal reflux. Gastroesophageal reflux is one of the most common of all diseases, affecting up to a quarter of all adults, and Barrett's oesophagus itself occurs in 0.5 - 1% of the adult population. In a minority of patients wit ....The oesophagus (gullet) is the tube through which food and drinks pass from the mouth to the stomach. In Barrett's oesophagus, the normal lining of the lower oesophagus is replaced by an abnormal type of lining called intestinal metaplasia as a result of severe gastroesophageal reflux. Gastroesophageal reflux is one of the most common of all diseases, affecting up to a quarter of all adults, and Barrett's oesophagus itself occurs in 0.5 - 1% of the adult population. In a minority of patients with Barrett's oesophagus, further abnormalities in the cells lining the lower oesophagus occur, leading to dysplasia and adenocarcinoma (glandular cell type cancer). This project will provide the first comprehensive map of two of the most important genetic mechanisms (gene expression and DNA methylation) by which Barrett's oesophagus evolves into Barrett's dysplasia and adenocarcinoma. The specimens studied in this project differ from previous studies in that they are taken from the same patients at different times, as these patients' Barrett's oesophagus either remains stable or progresses to worse disease. Essentially all the known human genes will be studied and the relevance of genes identified as important will be confirmed using highly accurate methods. With this information, it may be possible to develop genetic tests that can predict which patients are at risk of developing worse disease including cancer. In other parts of this project, genes which influence the likelihood of survival for patients with oesophageal adenocarcinoma will be identified, a simple test to more accurately identify patients with cancer spread to lymph nodes may be developed, and a blood test to detect oesophageal adenocarcinoma will be tested.Read moreRead less
Risk Factors For Gastro-oesophageal Reflux Disease And Barretts Oesophagus In A Prospective Cohort Study
Funder
National Health and Medical Research Council
Funding Amount
$960,867.00
Summary
Heartburn caused by acid reflux is a common problem in Australia. In 2003, drugs used to treat disorders caused by acid problems, such as heartburn, cost the PBS more than $500 million. Heartburn probably causes a disease of the oesophagus called Barrett's oesophagus, which in turn is a cause of cancer of the oesophagus. The aim of this study is to identify risk factors for heartburn and Barrett's oesophagus, so that we can find ways to prevent them occurring.
BEST-Australia: A Phase II Study Of Non-Endoscopic Screening For Barretts Oesophagus In Primary Care
Funder
National Health and Medical Research Council
Funding Amount
$513,481.00
Summary
Barrett's oesophagus is common in people with heartburn and may progress to oesophageal cancer. Most cases of oesophageal cancer are diagnosed at a late stage when chances of survival are poor. Currently Barrett's is only diagnosed by endoscopy. We will test how effective and acceptable a non-endoscopic sponge capsule and novel laboratory test is at detecting Barrett's oesophagus early. This could potentially enable early detection of this pre-cancerous condition in general practice.
Barrett's oesophagus (BO) is a condition that arises in some patients with chronic reflux (heartburn) and increases the risk of developing cancer of the oesophagus. However, the exact mechanisms involved in its development are unknown. This project aims to investigate how a protein called sonic hedgehog might be involved using novel cell culturing techniques that allow us to model the growth of oesophageal tissue in the laboratory. This could lead to development of new therapies for treating BO.
In Vivo Models For Understanding The Cellular And Molecular Pathogenesis Of Barrett's Oesophagus
Funder
National Health and Medical Research Council
Funding Amount
$283,767.00
Summary
The incidence of oesophageal adenocarcinoma, a malignancy that is almost invariably fatal, has doubled in recent years and continues to increase at an alarming rate. Oesophageal adenocarcinoma arises from Barrett's oesophagus, a premalignant condition that effects up to 2% of the population. In Barrett's, the normal cells of the oesophageal lining are changed to become more like cells that line the intestine. We have developed novel 3-dimensional cell culture models that allow us to reproduce th ....The incidence of oesophageal adenocarcinoma, a malignancy that is almost invariably fatal, has doubled in recent years and continues to increase at an alarming rate. Oesophageal adenocarcinoma arises from Barrett's oesophagus, a premalignant condition that effects up to 2% of the population. In Barrett's, the normal cells of the oesophageal lining are changed to become more like cells that line the intestine. We have developed novel 3-dimensional cell culture models that allow us to reproduce the normal layered structure of the human oesophageal lining in the laboratory and we propose to use these models to address key issues in the biology of Barrett's oesophagus. In aim 1, we wish to determine if the cells in patients with Barrett's have been permanently, or only transiently, altered and to understand the role of gastric acid- bile and accessory cells in this transformation. In aim 2 we will look more closely at the molecular changes that drive the cellular transformation characteristic of Barrett's. We will do this by manipulating the expression of selected genes in human oesophageal cells and assessing the effects of these genes on cell growth and differentiation using our cell culture models. The results of these studies will pave the way for the design of appropriate clinical strategies to treat Barrett's oesophagus and prevent the progression of this premalignant condition to oesophageal adenocarcinoma.Read moreRead less
Barrett's Oesophagus And Reflux Oesophagitis : Efficacy Of Medical Vs Surgical Management
Funder
National Health and Medical Research Council
Funding Amount
$510,750.00
Summary
Gastro-oesophageal reflux disease is very common. In some people it leads to oesophageal cancer, which is increasing in incidence more rapidly than any other cancer in the developed world. Significant resources are required for its diagnosis, surveillance and treatment. There are two main forms of treatment, acid suppressing drugs which may be required for the rest of the person's life, or surgery. The goal of treatment is the control of the symptoms such as heartburn, and the prevention of canc ....Gastro-oesophageal reflux disease is very common. In some people it leads to oesophageal cancer, which is increasing in incidence more rapidly than any other cancer in the developed world. Significant resources are required for its diagnosis, surveillance and treatment. There are two main forms of treatment, acid suppressing drugs which may be required for the rest of the person's life, or surgery. The goal of treatment is the control of the symptoms such as heartburn, and the prevention of cancer. It is relatively easy to determine if the symptoms are controlled, and both medical and surgical treatments do this. It is not as easy to measure if a treatment will reduce the risk of cancer, because it takes so long to develop. We will compare a group of patients with reflux disease treated with drugs with a group treated by surgery. In each group we will take oesophageal tissue before treatment and compare it with similar tissue taken after treatment. We will look for reductions in abnormal cells and genes that are in diseased tissue and are important in the development of cancer. This study will help us understand the mechanisms by which reflux causes damage to the oesophagus and how it ultimately leads to cancer. We will learn if medical or surgical treatment is better in healing the underlying damage in the oesophagus, and which treatment is more likely to prevent cancer developing. It may result in more effective management of reflux in our community and help reduce the number of cases of oesophageal cancer.Read moreRead less
Ablative Therapies For Barrett's Oesophagus - Evaluation Of New Clinical And Experimental Therapies
Funder
National Health and Medical Research Council
Funding Amount
$302,310.00
Summary
Barrett's oesophagus arises when repeated episodes of gastro-oesophageal reflux lead to the oesophageal lining undergoing change to a lining more like that of the intestine. This new lining predisposes to cancer, a problem which is rapidly becoming more common. Recent research has focused on techniques which could reverse this process. Destruction (ablation) of Barrett s oesophagus can be followed by regeneration with a normal looking lining. A range of techniques have been used for this. Howeve ....Barrett's oesophagus arises when repeated episodes of gastro-oesophageal reflux lead to the oesophageal lining undergoing change to a lining more like that of the intestine. This new lining predisposes to cancer, a problem which is rapidly becoming more common. Recent research has focused on techniques which could reverse this process. Destruction (ablation) of Barrett s oesophagus can be followed by regeneration with a normal looking lining. A range of techniques have been used for this. However, the behavior of the regenerated lining is unknown, and there still remains potential for cancer. We are currently evaluating endoscopic ablation using Argon Plasma Coagulation within clinical trials. There is also scope for the development of better approaches to ablation. We hypothesize that an suitable liquid has the potential to more evenly and more easily ablate the lining. Delivery of a liquid substance to lower oesophagus can be achieved through a tube which confines liquid to the lower oesophagus. However, to make this approach acceptable it is necessary to determine the best treatment agent, and to test the delivery system. We will first do this using animal models, before future application in patients. A further key issue is whether the cells which repopulate the oesophagus are genetically normal or abnormal. After ablation it is likely that the cells which repopulate the lining are sourced from the same cells which were the source of the abnormal lining, and these cells could inherit genetic alterations. This could increase the risk of cancer. Hence, we plan to assess certain genes in biopsies taken from tissue before and after ablation to determine genetic normality. In Australia endoscopic ablative techniques are currently being introduced into clinical practice without evaluation. Hence the question of whether ablation actually reduces the risk of cancer and how to best perform ablation should be addressed before clinical application becomes widespread.Read moreRead less
Improving The Surgical Outcomes For Barretts-derived Oesophageal Adenocarcinoma Through Early Detection.
Funder
National Health and Medical Research Council
Funding Amount
$796,144.00
Summary
Some people with severe reflux develop Barrett's oesophagus, which puts them at high risk of developing cancer. Patients with Barrett's can be monitored by regular endoscopy to detect cancer early enough so that they can be treated successfully with surgery. The aim of this work is to identify patients who are at highest risk of cancer using molecular biomarkers. We will then determine the cost effectiveness of using biomarkers for surveillance of patients with Barrett's oesophagus.
Pathophysiology And Treatment Of Pharyngo-oesophageal Dysfunction
Funder
National Health and Medical Research Council
Funding Amount
$168,275.00
Summary
A number of oral and respiratory tract diseases such as laryngitis, asthma, unexplained cough, sinusitis, and obstructive sleep apnoea, have been linked with gastroesophageal reflux disease. These particular respiratory complications carry significant morbidity and mortality. The mechanisms of regurgitation of gastric acid, via the oesophagus into the pharynx, are unknown. We have recently validated a novel technique to reliably detect acid regurgitation events into the pharynx. We propose to us ....A number of oral and respiratory tract diseases such as laryngitis, asthma, unexplained cough, sinusitis, and obstructive sleep apnoea, have been linked with gastroesophageal reflux disease. These particular respiratory complications carry significant morbidity and mortality. The mechanisms of regurgitation of gastric acid, via the oesophagus into the pharynx, are unknown. We have recently validated a novel technique to reliably detect acid regurgitation events into the pharynx. We propose to use this technique, combined with pressure recordings from the oesophagus and its valves, to determine the precise mechanisms underlying acid regurgitation into the throat. Such studies should lead to better means of treating these disorders.Read moreRead less