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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
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