Molecular Characterisation And Diagnosis Of Malignant Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$421,250.00
Summary
Malignant mesothelioma (MM) is an aggressive, asbestos-related tumour of increasing incidence throughout the world that is estimated to be cause approximately 20,000 deaths per annum . MM was rare until approximately 20-30 years ago but it is now more, or as, common a cause of death in Australia as cancers of the bone, liver, cervix, bladder and ovary. Although asbestos use has declined to virtually zero across most of the developed world, due to 30 to 40 year latency of the disease, the peak in ....Malignant mesothelioma (MM) is an aggressive, asbestos-related tumour of increasing incidence throughout the world that is estimated to be cause approximately 20,000 deaths per annum . MM was rare until approximately 20-30 years ago but it is now more, or as, common a cause of death in Australia as cancers of the bone, liver, cervix, bladder and ovary. Although asbestos use has declined to virtually zero across most of the developed world, due to 30 to 40 year latency of the disease, the peak in cases of mesothelioma is not expected until 2010. MM is one of the most aggressive and debilitating tumours known, with a median survival of 7-10 months and a clinical pattern that usually involves substantial pain and dyspnea. Advances in therapy-prevention of mesothelioma will have not only have a major health impact, but potentially an extraordinary economic impact. MM is predicted to cost the Australian economy around $5 billion in compensation over the next 35-40 years. Government, insurance companies and industry will share that cost. The significance of this disease therefore extends beyond its actual incidence. There is growing evidence in many tumour types that the best diagnostics and treatments for cancer will come about as a result of understanding the molecular logic that underpins carcinogenesis, and designing therapies and diagnostics accordingly. We will carry out a project using the most comprehensive microarrays available to profile gene expression in malignant mesothelioma. We will use the expression data we obtain to fulfil three aims. Firstly, we will use patient outcome information to search for genes whose expression is indicative of response to therapy. Secondly, we will search the data to identify candidate secreted molecules which may be useful in the early detection of MM. Finally, we will develop a molecular assay to unequivocally diagnose MM from cells collected from pleural effusions.Read moreRead less
Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, ....Growth hormone is responsible for normal postnatal growth, is an important metabolic regulator in starvation, and has many useful therapeutic applications, including forms of cardiac insufficiency, Crohns disease and, it is thought, amelioration of ageing. The means whereby GH brings about these changes are not known, although we do know a considerable amount about how the individual domains within the GH receptor signal. What we do not know is which genes are regulated by GH in these processes, and how this will change the state of the cell. We propose here to use the new technique of gene arrays to uncover the programs, or groups of genes, which GH regulates to change important cellular processes. When used in conjunction with cells expressing GH receptor mutants which are unable to signal to defined pathways, we will be able to know which functional families genes are regulated, and how they are regulated. This information will enable us to know how GH regulates cell growth and metabolism, and therfore to understand what goes wrong when GH or its mediator, IGF-1 , are abnormal. We can also use this information to validate small molecules designed to mimic GH through activating its receptor, to be certain that they are acting in the same way as GH.Read moreRead less
Molecular Classification Of Carcinoma Of Unknown Primary
Funder
National Health and Medical Research Council
Funding Amount
$418,250.00
Summary
Carcinoma of unknown primary (CUP) is the fourth largest cause of cancer death. The condition has a particularly poor outlook, with a median survival of less than one year. Current methods for diagnosis of CUP include histopathology and sophisticated imaging. These are successful in approximately 40% of cases. Frequently the reason for the poor outcome in this disease is that the 60% of patients with CUP for whom no diagnosis is made do not benefit from chemotherapy specifically designed for a p ....Carcinoma of unknown primary (CUP) is the fourth largest cause of cancer death. The condition has a particularly poor outlook, with a median survival of less than one year. Current methods for diagnosis of CUP include histopathology and sophisticated imaging. These are successful in approximately 40% of cases. Frequently the reason for the poor outcome in this disease is that the 60% of patients with CUP for whom no diagnosis is made do not benefit from chemotherapy specifically designed for a particular tumour origin. These patients receive a less effective, generic, chemotherapy. The aim of this project is to use microarrays to identify the gene expression profile in many known tumours to create a molecular fingerprint of the various tumour types. By comparing the fingerprint from a CUP with the database we should be able to identify the true tumour type in CUP, and allow patients to benefit from more specific chemotherapy.Read moreRead less
Preventing Myocardial Infarction: A Mouse Model Of Atherosclerotic Plaque Instability/rupture As Unique Tool For Establishing Novel Pharmacological Strategies And Targeted Molecular Imaging
Funder
National Health and Medical Research Council
Funding Amount
$586,965.00
Summary
Myocardial infarction strikes without warning and thereby causes death or major disability. It is typically caused by sudden rupture of atherosclerotic plaques and occlusion of coronary arteries. Research on this was hampered by the lack of an animal model of plaque rupture. We have newly established a mouse model, which we will now use to generate novel tools to image and identify plaques that are prone to rupture and to develop novel therapies preventing plaque rupture and myocardial infarctio ....Myocardial infarction strikes without warning and thereby causes death or major disability. It is typically caused by sudden rupture of atherosclerotic plaques and occlusion of coronary arteries. Research on this was hampered by the lack of an animal model of plaque rupture. We have newly established a mouse model, which we will now use to generate novel tools to image and identify plaques that are prone to rupture and to develop novel therapies preventing plaque rupture and myocardial infarction.Read moreRead less
Identification And Characterisation Of Amplified Oncogenes In Liposarcoma
Funder
National Health and Medical Research Council
Funding Amount
$354,293.00
Summary
Liposarcoma is the commonest single subtype of sarcomas, a group of cancers that disproportionately affects the young. The overall mortality for liposarcomas is approximately 50%. Chemotherapy may temporarily controlling disease in under a third of patients, but is toxic and cannot achieve cure. We have identified new potential therapeutic targets, and aim to develop these in the clinic.
The Role Of NF-kB Transcription Factors In Regulating T Cell Transcription Networks
Funder
National Health and Medical Research Council
Funding Amount
$534,000.00
Summary
T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. T ....T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of proteins known as transcription factors. One family of transcription factors that plays a key role in T cell function is the NF-kB family consisting of five different members, three of which are important in T cell function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed knowledge of the biology of these factors through studies of mice lacking specific family members. While we know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we need a global view of NF-kB action in the cell. This proposal uses both experimental and computational approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB pathway.Read moreRead less
MECHANISMS OF PATHOLOGY AND NEW THERAPEUTIC OPTIONS FOR GAUCHER DISEASE AND OTHER LIPIDOSES
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
The sphingolipidoses are a subgroup of the more than 45 genetic disorders known collectively as lysosomal storage disorders (LSD). As a result of the deficiency of specific enzymes or proteins involved in the breakdown of sphingolipids (fats), there is an accumulation of this material in affected cells. These diseases can affect liver, spleen, kidney, bone and the central nervous system. Gaucher disease is the prototype for the sphingolipidoses and, in this project, we will use this disease as a ....The sphingolipidoses are a subgroup of the more than 45 genetic disorders known collectively as lysosomal storage disorders (LSD). As a result of the deficiency of specific enzymes or proteins involved in the breakdown of sphingolipids (fats), there is an accumulation of this material in affected cells. These diseases can affect liver, spleen, kidney, bone and the central nervous system. Gaucher disease is the prototype for the sphingolipidoses and, in this project, we will use this disease as a model for this group of disorders. Gaucher disease in the most prevalent LSD with an incidence of 1:56,00 births, worldwide there are approximately 2300 affected individuals born each year. Enzyme replacement therapy (ERT) for Gaucher disease has been successful in the treatment of the non-neuropathic form of the disease. However ERT is expensive ($200,000-400,000 pa). There are approximately 50 Australian patients undergoing ERT at a cost of at least $10 million per annum. However, due to the high cost of treatment, many people do not qualify for ERT, despite having serious medical problems. Worldwide, there are approximately 4000 people currently receiving ERT for Gaucher disease at a total drug cost of over $1.0 billion pa. However, based on birth rates and life expectancies there are over 80,000 Gaucher patients in the world. With the current cost of ERT it is likely that over 90% of these will never receive ERT. If therapy is to be made available for the majority of affected individuals, cheaper alternatives will be required. In this project we will use cellular models of Gaucher disease to study the processes leading to the disease and to develop alternative, cheaper therapies for this disease and other types of sphingolipidoses, for which no therapies currently exist.Read moreRead less
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