DNA methylation-based diagnosis of cancer and identification of novel therapeutic targets. In our aging society, cancer represents a severe economic and quality-of-life threat. DNA methylation switches genes off, and recently, it was shown that defects in DNA methylation contribute to human diseases including cancer. This project will identify defects in DNA methylation associated with cancer. Identifying these defects will enable us to design non-invasive, early diagnostic tests for cancer on b ....DNA methylation-based diagnosis of cancer and identification of novel therapeutic targets. In our aging society, cancer represents a severe economic and quality-of-life threat. DNA methylation switches genes off, and recently, it was shown that defects in DNA methylation contribute to human diseases including cancer. This project will identify defects in DNA methylation associated with cancer. Identifying these defects will enable us to design non-invasive, early diagnostic tests for cancer on blood or bodily excretions, and to pursue novel therapeutic approaches for treating cancer. The expected outcomes would generate exports to markets in the USA and Europe and replace imports of drugs and technology to treat cancer.Read moreRead less
Molecular hallmarks of androgen receptor targeting in prostate cancer. There is a critical need in oncology drug development for better biomarkers of response to prostate cancer therapies, clinically to assist with treatment decision making, and pre-clinically to facilitate translation of emerging agents into clinical practice. Using a unique explant culture model, this project will identify protein and lipid markers that can be used to accurately and reliably assess response to androgen recepto ....Molecular hallmarks of androgen receptor targeting in prostate cancer. There is a critical need in oncology drug development for better biomarkers of response to prostate cancer therapies, clinically to assist with treatment decision making, and pre-clinically to facilitate translation of emerging agents into clinical practice. Using a unique explant culture model, this project will identify protein and lipid markers that can be used to accurately and reliably assess response to androgen receptor (AR)-targeting therapies in human prostate tumours. The identification and functional assessment of these biomarkers will identify those that can be used as surrogate endpoints in clinical trials, facilitate earlier approval of investigational agents and lead to improved options for therapeutic management of prostate cancer.Read moreRead less
Tumour Suppressor Networks: The Role Of SHIP-1 And Lyn In Suppressing Haematopoietic Tumours
Funder
National Health and Medical Research Council
Funding Amount
$469,526.00
Summary
Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in ....Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in some instances Lyn and SHIP-1 participate in the same biochemical pathway. We have created mice that are unable to make Lyn protein, and have found that these mice develop blood cell tumours. Mice lacking SHIP-1 develop a number of haematological defects, but die at a young age due to an inflammatory lung condition, making an assessment of the role of SHIP-1 in age-dependent tumour development difficult. We now wish to study the role of SHIP-1 in tumour development, by generating mice that lack SHIP-1 in specific white blood cell compartments. We are also investigating how SHIP-1 and Lyn cooperate in tumour suppression, and we have recently generated mice that simultaneously lack both SHIP-1 and Lyn. Preliminary studies indicate that compound mutant mice develop multiple haematological malignancies. We will fully characterize tumour development in these animals, and determine the molecular basis for this pathology. We will focus on two pathways that have been previously implicated in oncogenesis. These studies will improve our insight into how Lyn and SHIP-1 cooperate in blood cell development, cellular homeostasis and oncogenesis, and add to our biological and biochemical understanding of tumour suppressor networks.Read moreRead less
Molecular Identification Of Causative Genetic And Epigenetic Alterations That Induce And Promote Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$381,821.00
Summary
The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that under ....The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that underpin the probable cause of colon cancer. We therefore propose to genetically engineer unique mouse models that focus on colon cancer to most closely replicate the situation in human disease. These models will then be available to others and us to develop and test therapies to prevent and-or treat colorectal cancer that will ultimately be used in patients.Read moreRead less
The Role Of PIPP In Cell Polarization And Proliferation.
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon stimulation, a series of signals are generated inside the cell which lead to cell division and development. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. Following growth factor stimulation, P ....Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon stimulation, a series of signals are generated inside the cell which lead to cell division and development. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. Following growth factor stimulation, PI3-kinase generates a molecule known as PtdIns(3,4,5)P3 which leads to the activation of many proteins in the signaling pathway. All cells which have PI3-kinase also have enzymes which act to switch off the signals generated by PI3-kinase and thus may play a role in preventing cancer and regulating cell development. We have identified a new enzyme known as PIPP and have shown that it acts to switch off the signals generated by PI3-kinase. We plan to investigate the role of PIPP by increasing or decreasing the amount of PIPP in cells and analysing the effects on cell growth and development. We have also identified a number of proteins which bind to PIPP and we will investigate the role these proteins play in regulating cell signaling. In addition, we plan to characterize the function of PIPP in a whole animal by generating mice which lack PIPP (knockout mice) and assessing the effects on development and cancer.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE140100166
Funder
Australian Research Council
Funding Amount
$370,000.00
Summary
Imaging Cell and Tissue Architecture using Confocal and Super-Resolution Microscopy. Imaging cell and tissue architecture using confocal and super-resolution microscopy: This project aims to understand how the architecture of cells and tissues is controlled. This is because the organisation of biological space underpins the function of cells, tissues and organisms. This project will test the role of identified parts of cell architecture in regulating specific animal functions/pathologies. It wil ....Imaging Cell and Tissue Architecture using Confocal and Super-Resolution Microscopy. Imaging cell and tissue architecture using confocal and super-resolution microscopy: This project aims to understand how the architecture of cells and tissues is controlled. This is because the organisation of biological space underpins the function of cells, tissues and organisms. This project will test the role of identified parts of cell architecture in regulating specific animal functions/pathologies. It will do this by using new microscope technologies which are at the frontier of visualising cell structure in isolation and in the context of tissue including application to the living animal. The dynamic organisation of structures in cells will be imaged in living tissue. Novel insights into structure/function relationships in the body will impact the health industry and generate opportunities for new diagnostics and therapeutics. Read moreRead less
Characterisation Of The Role & Biomarker Potential Of The Novel Cell Surface Protein TTYH2 In Renal Cell Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$489,000.00
Summary
Renal cell carcinoma is the most common cancer of the kidney. One-third of patients upon first diagnosis have secondary tumour sites already within their body as well as new treatment approaches for more advanced disease making them very difficult to cure. An early specific test for this cancer is urgently needed. Our group has identified a new gene called TTYH2 which is highly expressed by renal cell carcinoma tissue samples but not in normal kidney tissues. In this study, we intend to look at ....Renal cell carcinoma is the most common cancer of the kidney. One-third of patients upon first diagnosis have secondary tumour sites already within their body as well as new treatment approaches for more advanced disease making them very difficult to cure. An early specific test for this cancer is urgently needed. Our group has identified a new gene called TTYH2 which is highly expressed by renal cell carcinoma tissue samples but not in normal kidney tissues. In this study, we intend to look at the expression of TTYH2 in more clinical samples to determine if TTYH2 will be a useful bio-marker for this cancer. We are also studying the function of this protein in renal cell carcinoma cells to identify the exact role that TTYH2 performs in cancer development and progression. Finally we will look at what other proteins are interacting with TTYH2 in kidney cancer cells. These latter studies will help us to understand the disease process better and may help us design new treatment methods.Read moreRead less
A Clinical Trial To Determine The Optimal Timing Of Androgen Deprivation In Relapsed Or Non-curable Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$627,600.00
Summary
The aim of the study is to clarify when is the optimal time to start hormone treatment for men with certain stages of prostate cancer. It has long been known that testosterone removal impedes prostate cancer growth, although not permanently. The removal of testosterone, however, has side effects , including loss of libido, hot flushes, weight gain, and in the longer term osteoporosis, loss of muscle bulk and mental changes such as loss of memory. Any benefit to be gained for a patient must there ....The aim of the study is to clarify when is the optimal time to start hormone treatment for men with certain stages of prostate cancer. It has long been known that testosterone removal impedes prostate cancer growth, although not permanently. The removal of testosterone, however, has side effects , including loss of libido, hot flushes, weight gain, and in the longer term osteoporosis, loss of muscle bulk and mental changes such as loss of memory. Any benefit to be gained for a patient must therefore be weighed against these side effects. This is particularly relevant in situations in which cure is not possible, when the aim of treatment should be to manage symptoms (either by preventing or delaying them or treating them as they arise). There are two situations in which a man may be diagnosed as having active prostate cancer but be without symptoms requiring immediate treatment. The first is after the failure of curative treatment, shown by the presence of prostate specific antigen (PSA) in the blood, but without any other evidence of prostate cancer. The second is a man newly diagnosed with asymptomatic prostate cancer, but with other reasons (such as heart disease) which make an attempt at cure inappropriate. We do not know in either case whether or not men live longer if treatment is started immediately, or whether it is reasonable to wait until symptoms develop, thus potentially postponing the side effects of treatment. The trial will therefore include these two groups of men. Half the men will be randomised to receive immediate treatment, and half to treatment starting when symptoms develop, or when there is evidence of progressive disease. The main endpoint is overall survival, balanced against quality of life and side effects from the disease and treatment. The hypothesis is that early treatment will improve survival with acceptable effects on quality of life.Read moreRead less
Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the exte ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less
A new Src, PKCdelta and Akt regulated protease activated receptor system in metastasis. In contrast with localised cancer which can often be cured, curative treatment is generally not possible for cancer that has spread. This project will characterise a protein that drives the spread of cancer and to develop new approaches to treat patients at risk of developing these aggressive tumours that spread to other organs.