Mechanisms Of CD44v2-10-mediated Tumour Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to investigate the mechanisms by which specificdomains in the CD44 variants actually cause tumour spread. Understanding of the various mechanisms involved in tumour spread, and targeting the functions of the domains has enormous potential as a therapeutic target.Read moreRead less
CD44v3 And V6 As Targets For Anti-metastasis Therapy
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to develop a number of specific methods of targeting CD44 in order to prevent the spread of cancer. We have and will develop additional agents directed to these key domains in CD44. Targeting these domains has great potential as metastasis therapy.Read moreRead less
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
Predicting Response To Chemoradiotherapy In Patients With Advanced Rectal Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$461,605.00
Summary
Many cancer patients receive expensive and unpleasant therapies that actually do not benefit them. This project will use a new technology that can simultaneously assess the level of expression of thousands of genes. We will test if the pattern of gene expression in tumours can predict the patients' response to therapy. Success will significantly improve the clinical management of advanced cancer patients and provide a rational basis upon which to tailor individualized treatment regimes.
Optimizing Implanted Cell Survival Using A Tissue Engineering Model
Funder
National Health and Medical Research Council
Funding Amount
$589,175.00
Summary
Cell therapy and tissue engineering involve the insertion of specific cells into damaged tissues or into a bioraector in a patient's body to generate new replacement tissues. This project seeks to improve two factors associated with inserting cells : 1. The innate survival characteristics of the cells being inserted, and 2. The blood vessel supply at the site of insertion. These techniques will greatly improve the survival of inserted cells.
The Use Of Gene Expression Profiles To Predict The Response To Chemoradiotherapy In Patients With Oesophageal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$384,600.00
Summary
One of the most difficult and clinically important questions facing clinicians treating advanced cancer is deciding which patients will, and who will not, benefit from chemotherapy and-or radiotherapy. This is particularly true for clinicians treating locally advanced oesophageal cancer. Oesophageal cancer is a particularly aggressive tumour with a poor prognosis; the majority of patients die within 1 year of diagnosis with only 10% surviving to 5 years. In an attempt to improve outcomes, the us ....One of the most difficult and clinically important questions facing clinicians treating advanced cancer is deciding which patients will, and who will not, benefit from chemotherapy and-or radiotherapy. This is particularly true for clinicians treating locally advanced oesophageal cancer. Oesophageal cancer is a particularly aggressive tumour with a poor prognosis; the majority of patients die within 1 year of diagnosis with only 10% surviving to 5 years. In an attempt to improve outcomes, the use of preoperative (neoadjuvant) combined chemotherapy and radiotherapy as an adjunct to surgery has become common practice. Neoadjuvant therapy has been reported to induce complete regression of the tumour and increased survival times in 20-30% of patients. However, the lack of any apparent clinical benefit for those patients who are poor or non-responders to chemoradiation implies that a large proportion of patients are being exposed to significant toxicity and potential complication for no obvious advantage. In the project outlined in this application, we propose to use cDNA microarrays, a technology that allows the simultaneous assessment of the level of expression of thousands of genes at once, to profile the gene expression patterns of oesophageal tumours. These profiles will then correlated to the patients response to treatment to determine if the gene expression patterns can be used to predict the clinical response to chemoradiotherapy. Success will open the path to the development of a clinically important test that would significantly improve the management of advanced cancer patients by enabling personalised therapy for individual patients. Not only will this allow the selection of the most effective therapy for each patient but it will also free patients from suffering the nasty side effects of treatments that turn out to be of little benefit.Read moreRead less
Evaluation A Novel Vitronectin:growth Factor Complex For Treatment Of Chronic Venous Leg Ulcers
Funder
National Health and Medical Research Council
Funding Amount
$854,975.00
Summary
Chronic leg ulcers in the elderly are an important problem, diminshing quality of life and costing at least A$1 billion per year. New treatments are urgently required. This study will test a new topical growth factor therapy designed to have greatly improved activity in wounds.The project is a collaboration between scientists and doctors at the Queensland Univeristy of Technology and the University of Western Australia. Many wound types may ultimately benefit from this treatment.
Clinical Feasibility Study Of Omega-3 PUFA Therapy For The Reduction Of Post-cardiac Surgery Atrial Arrhythmias
Funder
National Health and Medical Research Council
Funding Amount
$442,092.00
Summary
The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids (PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale, placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids (PUFA). Recently, omega-3 PUFA via fish diet was reported to be li ....The aim of this study is to determine the molecular and clinical impact of omega-3 polyunsaturated fatty acids (PUFA) pre-treatment 2 weeks before cardiac surgery in 150 patients. The outcome of this proposal will indicate proof of molecular concepts, clinical feasibility and specific design elements of a future, large scale, placebo controlled, prospective randomised trial of oral therapy with omega-3 polyunsaturated fatty acids (PUFA). Recently, omega-3 PUFA via fish diet was reported to be linked to low incidence of AF. The main aim is to provide a cheap and safe preventative therapy against post-operative atrial fibrillation (AF), a key heart rhythm disorder that occurs in at least 1 in 4 patients after heart surgery and increases post-operative complications, limits recovery and increases hospital stay and cost. Biochemical study elements are important to gain valuable insight into the molecular mechanisms (directly in human heart) that underlie post-operative heart rhythm disorder and may delineate new more precise molecular targets for therapy. No previous clinical study has ever examined whether omega-3 PUFA therapy prevents post-operative heart rhythm disorder. Use of 3g-day omega-3 PUFA pre-treatment in the surgical setting has been shown to be safe in a number of small studies, including our own. Our preliminary data indicates that therapy increases heart and blood content of omega-3 PUFA ~2-fold, and reduces the incidence of AF. Post-operative AF is an expensive resource burden in all cardiothoracic surgery units of Australian hospitals and targets key health priorities. Due to the non-patentable nature of omega-3 PUFA, significant industry based support for clinical research is limited. A positive outcome would rapidly pave the way for widespread use in elective surgery. Reduced length of hospital stay, cost-savings, and the increase in productivity as healthy individuals return to their communities would nationally repay the investment many fold.Read moreRead less