Integrating Conventional Mesothelioma Therapies With Immuno- And Gene-therapies
Funder
National Health and Medical Research Council
Funding Amount
$804,916.00
Summary
Asbestos-induces cancers are some of the most aggressive cancers know to medicine. Unfortunately, treatments are not very effective and it is unusual for these cancers to be cured, particularly mesothelioma. Because recent scientific studies have suggested that combinations of therapy which include immunotherapy, ie treatments aimed at stimulating the bodies anti-cancer immune responses to attack the cancer, can be effective, we plan to develop this work in order to determine exactly which combi ....Asbestos-induces cancers are some of the most aggressive cancers know to medicine. Unfortunately, treatments are not very effective and it is unusual for these cancers to be cured, particularly mesothelioma. Because recent scientific studies have suggested that combinations of therapy which include immunotherapy, ie treatments aimed at stimulating the bodies anti-cancer immune responses to attack the cancer, can be effective, we plan to develop this work in order to determine exactly which combinations are likely to be the most effective and therefore the most suitable for clinical trial in patients.Read moreRead less
A National Resource For Mouse Models Of Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$483,643.00
Summary
Mouse models of mesothelioma have led to a greater understanding of the disease and the identification of potential drug therapies some of these have now been translated into clinical trials. In the existing models, mesothelioma cells that have been grown in the laboratory are transplanted into animals by injecting the cells under the skin. Different cell lines with different properties are used in different experimental protocols. This application will fund the establishment of a central resour ....Mouse models of mesothelioma have led to a greater understanding of the disease and the identification of potential drug therapies some of these have now been translated into clinical trials. In the existing models, mesothelioma cells that have been grown in the laboratory are transplanted into animals by injecting the cells under the skin. Different cell lines with different properties are used in different experimental protocols. This application will fund the establishment of a central resource to maintain and distribute these cell lines. In addition, we describe a new transgenic mouse model in which mesotheliomas are rapidly induced in the peritoneal cavity after exposure to asbestos, recreating the natural tumour development much more accurately. These mice have been engineered to express the cancer causing protein of a monkey virus (SV40 large T antigen) in their mesothelial cells because it has been suggested that the virus has a role in the development of mesothelioma. This application also seeks funding to use the MexTAg mice to test the usefulness of different therapies for the prevention or treatment of mesothelioma. These animals give us the ability to investigate the disease in a more realistic environment than previous models. In parallel collaborative studies with other groups investigating different aspects of the biology of this cancer, we plan to analyze the earliest changes in the development of the disease and search for early markers using proteomics and gene expression studies. We anticipate that this model will generate information more directly relevant to understanding the human disease and will provide essential experimental data for clinical trials.Read moreRead less
Sensitive Serum Markers For Improved Diagnosis, Monitoring And Screening For Early Detection Of Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$410,880.00
Summary
The deadly asbestos-induced cancer mesothelioma is continuing to kill tens of thousands of individuals per year and its incidence is increasing. Mesothelioma is predicted to cost communities hundreds of billions of dollars in compensation. This disease is unusually difficult to diagnose and tends to be already quite advanced by the time patients present to the doctor with symptoms. Unfortunately, treatment options for the majority of patients are limited and most die within a year of diagnosis. ....The deadly asbestos-induced cancer mesothelioma is continuing to kill tens of thousands of individuals per year and its incidence is increasing. Mesothelioma is predicted to cost communities hundreds of billions of dollars in compensation. This disease is unusually difficult to diagnose and tends to be already quite advanced by the time patients present to the doctor with symptoms. Unfortunately, treatment options for the majority of patients are limited and most die within a year of diagnosis. In different forms of cancer, levels of certain proteins in the blood can be measured and have been shown to indicate the presence of tumour and in some cases the extent of tumour. These proteins are collectively known as tumour markers. Tumour markers for ovarian, prostate, breast and other cancers are used by doctors to help with the diagnosis of specific cancers, to monitor the patients response to treatment and to give a valuable early warning of remission or relapse. There is no tumour marker currently used for patients with mesothelioma. We have shown in early studies published in the prestigious journal The Lancet that soluble mesothelin related protein (SMRP) is actually elevated in more than 75% of mesothelioma patients and in less than 2% of patients with other cancer and non-cancer lung diseases. In this current project we plan to extend our studies looking at blood levels of SMRP to see if they will help in the care of patients with mesothelioma. So far we have done most of the work in a particular group of patients, but it is vital that the work be extended to other groups with different types and durations of exposure to asbestos and to different areas of the country. As part of that we need to test how stable the molecule is in blood samples, because if it is not very stable it wont be a very pratical test. We also plan to look at some other markers that have been clinically useful in other forms of cancer and we will try to identify new, novel mesothelioma specific markers. This work has the potential to impact on patient care in many centres of the world.Read moreRead less
Establishment Of A Latrobe Valley Power Industry Cohort And Biospecimen Bank For The Study Of Asbestos Related Disease
Funder
National Health and Medical Research Council
Funding Amount
$614,466.00
Summary
The Latrobe Valley has been the site of Victoria�s electricity generation since the 1920�s. Very large amounts of asbestos were used in the construction of power stations and housing for the workers employed to build and operate them. Asbestos is known to cause a tumour of the lining of the lung cavity called mesothelioma. Mesothelioma is a highly debilitating tumour, with a median survival as low as seven months following diagnosis. Mesothelioma can occur in asbestos exposed individuals up to f ....The Latrobe Valley has been the site of Victoria�s electricity generation since the 1920�s. Very large amounts of asbestos were used in the construction of power stations and housing for the workers employed to build and operate them. Asbestos is known to cause a tumour of the lining of the lung cavity called mesothelioma. Mesothelioma is a highly debilitating tumour, with a median survival as low as seven months following diagnosis. Mesothelioma can occur in asbestos exposed individuals up to forty years following exposure, and as such, the peak number of cases of mesothelioma is not expected in Australia for another 10-20 years. The incidence of mesothelioma in the Latrobe Valley is several fold the state average. We will recruit a cohort of 5000 asbestos exposed former power industry workers, and provide information, support and smoking cessation campaigns. For 1000 of the most highly exposed we will offer annual testing for mesothelin, a protein in the blood which may indicate the presence of mesothelioma prior to a clinical diagnosis.Read moreRead less
Epidemiology And Community Consequences Of Asbestos Exposure In WA
Funder
National Health and Medical Research Council
Funding Amount
$879,876.00
Summary
We aim to explore the impact of asbestos exposure on the health of individuals using the Wittenoom workers and residents cohort studies and the Australian community with the formation of a new community based cohort study. Using data from the Wittenoom workers and residents studies, we will examine the impact of asbestos exposure on women�s health which has not been looked at before. We will examine if asbestos exposure affects psychosocial health and determine if long term supplementation with ....We aim to explore the impact of asbestos exposure on the health of individuals using the Wittenoom workers and residents cohort studies and the Australian community with the formation of a new community based cohort study. Using data from the Wittenoom workers and residents studies, we will examine the impact of asbestos exposure on women�s health which has not been looked at before. We will examine if asbestos exposure affects psychosocial health and determine if long term supplementation with Vitamin A for cancer prevention results in an increased risk of bone fractures. We will also examine the genetic susceptibility of asbestos related diseases in these cohorts, and create and validate an algorithm to derive measures of fibre counts from occupational histories. Earlier projections of mesothelioma in the general community have been based on extrapolations from disease incidence in the past. We intend collecting data on a new community based cohort, to examine the distribution of asbestos in the community in order to predict future cases of asbestos related disease and the perception, beliefs and knowledge that exists in the community of its potential health effects. With this new knowledge we will devise an intervention program with the aim of preventing future cases of asbestos related disease. As part of this process we will use a multimedia website as an information hub. This will allow us to experiment with the use of creative media to present personal and community experiences of living with asbestos and present scientific research and public health messages.Read moreRead less
Transforming Growth Factor Beta Signalling In Malignant Mesothelioma Growth And Collagen Production
Funder
National Health and Medical Research Council
Funding Amount
$509,917.00
Summary
Many cancers contain abundant connective tissue molecules called extracellular matrix (ECM) and data show that interaction of ECM with cells are important in the growth of cancers (1). Changes in expression of ECM and their receptors (integrins) have been associated with malignant changes in cells, enhanced tumour growth and resistance to chemotherapy (2,3). We have recently shown that inhibition of collagen, the most abundant ECM molecule produced by malignant mesothelioma (MM) cells, reduced M ....Many cancers contain abundant connective tissue molecules called extracellular matrix (ECM) and data show that interaction of ECM with cells are important in the growth of cancers (1). Changes in expression of ECM and their receptors (integrins) have been associated with malignant changes in cells, enhanced tumour growth and resistance to chemotherapy (2,3). We have recently shown that inhibition of collagen, the most abundant ECM molecule produced by malignant mesothelioma (MM) cells, reduced MM growth. How cancer cells regulate ECM production and control their growth is unclear but strong evidence suggests the growth factor transforming growth factor-beta (TGFB) plays an important role. We and others showed that MM cells secrete all forms (1-3) of TGFB, and TGFB1,2-like activity has been reported in pleural effusions from MM (4,5). All TGFB forms stimulate MM cells to grow and make ECM (6,7). We showed that high levels of collagen produced by MM are enhanced by TGFB. Small molecules called antisense oligonucleotides (AO) which blocked production of TGFB2 by cells, reduced MM cell growth in soft agar, a characteristic of cancer, and partially blocked MM growth in animal models (4,6). This was supported by studies using soluble TGFB type II receptors, which blocks TGFB1,3 (8), and our studies using TGFB2 specific antibodies, as both studies reduced tumour growth. These findings support a role for TGFB in MM growth. However, all TGFB forms can promote cell grow and collagen synthesis and therefore ways to block all TGFB forms are required to ensure maximal effect. This study will examine the effect of blocking common downstream signalling pathways of all three TGFB isoforms on MM collagen production and tumour growth. These pathways are activated when TGFB binds to its receptors sending messages to the nucleus of the cell to make collagen or grow. By identifying which TGFB signalling pathway is important, we may be able to design novel therapeutic approaches to help treat patients with this disease.Read moreRead less
The Genetic Understanding Of Asbestos Related Disorders (GUARD)
Funder
National Health and Medical Research Council
Funding Amount
$566,008.00
Summary
This proposal is to build a new national biospeciman resource for mesothelioma research that will both underpin and enhance the national health and medical research effort in Australia by systematically enabling a world-class resource for genetic epidemiological research. The Genetic Understanding of Asbestos-Related Disorders (GUARD) project aims to establish a national facility that will enable new, large-scale DNA banking capacity for malignant mesothelioma (MM) and other asbestos-related dis ....This proposal is to build a new national biospeciman resource for mesothelioma research that will both underpin and enhance the national health and medical research effort in Australia by systematically enabling a world-class resource for genetic epidemiological research. The Genetic Understanding of Asbestos-Related Disorders (GUARD) project aims to establish a national facility that will enable new, large-scale DNA banking capacity for malignant mesothelioma (MM) and other asbestos-related diseases. The GUARD biospecimen resource and linked database will integrate the current WA population-based asbestos-exposed cohorts with case collections from across Australia. The GUARD project will undertake high-quality research aimed at discovering the genes and gene: environment interactions underlying susceptibility, progression and variable response to chemotherapy in mesothelioma, and will facilitate National collaboration and research in the areas of genetic epidemiology and pharmacogenomics. Progress towards the goals of the GUARD project holds the potential for enormous public health benefits; the incidence of malignant melanoma is increasing, due to the long delay between asbestos exposure and diagnosis. GUARD will ensure that Australian researchers have access to a large and well-managed biospecimen resource linked to excellent clinical data, and that Australia takes the lead role internationally in genetic research into mesothelioma. GUARD data will be critical for understanding the importance and functional roles of specific genes in the general Australian population, and their relationship to particular environmental factors. Understanding how causal factors act at a population level will be a critical step for the clinical utilization of new genomic knowledge and tools to improve clinical practice and public health.Read moreRead less
Role Of FLT PET In Malignant Pleural Mesothelioma - Prediction Of Response To Chemotherapy
Funder
National Health and Medical Research Council
Funding Amount
$93,639.00
Summary
Mesothelioma is a cancer of the lining of the lung. Chemotherapy is often used to treat patients in order to reduce their symptoms and to improve quality and length of life. Not all patients however benefit from chemotherapy, and most patients will experience some side-effects. Currently CT scans are used to assess response to chemotherapy, however the way that mesothelioma grows makes measuring response difficult. CT scans also are not very sensitive in detecting response early - often 3 or 4 c ....Mesothelioma is a cancer of the lining of the lung. Chemotherapy is often used to treat patients in order to reduce their symptoms and to improve quality and length of life. Not all patients however benefit from chemotherapy, and most patients will experience some side-effects. Currently CT scans are used to assess response to chemotherapy, however the way that mesothelioma grows makes measuring response difficult. CT scans also are not very sensitive in detecting response early - often 3 or 4 cycles of treatment (3-4 months) are required before benefit is seen. A test that could predict which patients were benefiting after only 1 cycle (3-4 weeks) of chemotherapy would be a great advantage, and may spare some patients unnecessary and potentially toxic treatment. Fluorothymidine (FLT) is a radioactive tracer that, after injection into a vein, is taken up by dividing cells. Tumour cells usually divide more actively than surrounding normal cells, and therefore when a positron emission tomography (PET) scan is performed it will demonstrate the tumour as a 'hot spot'. The amount of FLT uptake into the tumour depends on how much DNA synthesis (active cell division) is occurring. After chemotherapy, if the tumour responds it would be expected that the amount of FLT in the tumour will reduce. This can be assessed by repeating the FLT PET scan after the first cycle of chemotherapy. This study aims to assess the ability of the change in FLT uptake in mesothelioma after 1 cycle of chemotherapy to predict response, as measured on CT scans, and patient outcomes such as quality of life and survival. It is hoped that if successful this type of scan may improve patient care by selecting those who are likely to benefit from chemotherapy early and avoid unnecessary toxicity to patients who will not benefit from the treatment.Read moreRead less