Exploring A New Way To Overcoming Endocrine Resistance In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$441,764.00
Summary
Despite significant improvements in long-term outcome with the use of endocrine therapy (such as tamoxifen and letrozole), breast cancer remains the most common cause of cancer-related death amongst Australian women. A major clinical problem limiting the effectiveness of endocrine therapy is tumour resistance, either intrinsic or acquired. Indeed, about half of patients immediately fail to respond to the treatment, while in the initially responding patients the tumours ultimately progress to res ....Despite significant improvements in long-term outcome with the use of endocrine therapy (such as tamoxifen and letrozole), breast cancer remains the most common cause of cancer-related death amongst Australian women. A major clinical problem limiting the effectiveness of endocrine therapy is tumour resistance, either intrinsic or acquired. Indeed, about half of patients immediately fail to respond to the treatment, while in the initially responding patients the tumours ultimately progress to resistance to the drug leading to the disease relapse. Therefore, it is imperative to better understand the mechanisms responsible for the resistance and to explore new strategies that overcome this clinical problem in order to prolong the overall survival of patients with breast cancer. Our recent work have shown that a recently-identified enzyme, termed sphingosine kinase, plays an important role in promoting breast cancer cell growth. We also found that cells that have a high level of the enzyme had bad outcomes in response to anti-estrogen drug, tamoxifen. Thus this project seeks to identify the role of this enzyme in contributing towards drug resistance, and test if inhibition of this enzyme could improve and-or restore the drug response in breast cancer. It will ultimately pave a new way to overcoming the drug resistance for improving the treatment and prevention of breast cancer.Read moreRead less
Validating A New Model For Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflam ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.Read moreRead less
Xenotransplantation Of Encapsulated Insulin-producing Pig Cells
Funder
National Health and Medical Research Council
Funding Amount
$763,316.00
Summary
The ideal treatment for insulin-dependent diabetes is the replacement of insulin-producing cells. Currently, this is carried out using a whole pancreas or experimentally with cells isolated from the pancreas of donor humans. Despite the success of these procedures, demand for human organs far exceeds supply, thus driving the search for suitable alternatives. Pigs are physiologically similar to humans, and insulin-producing cells can be easily isolated from the fetal pig pancreas as islet-like ce ....The ideal treatment for insulin-dependent diabetes is the replacement of insulin-producing cells. Currently, this is carried out using a whole pancreas or experimentally with cells isolated from the pancreas of donor humans. Despite the success of these procedures, demand for human organs far exceeds supply, thus driving the search for suitable alternatives. Pigs are physiologically similar to humans, and insulin-producing cells can be easily isolated from the fetal pig pancreas as islet-like cell clusters; 8% of the cells in the cluster produce insulin and the remaining cells develop this capability after transplantation. Transplantation requires chronic immunosuppression with drugs which increase the risk of infection and cancer. To many people with diabetes, the side effects will be greater than the potential benefit. Placing cells inside microcapsules made of a biologically inert material may prevent graft rejection without chronic immunosuppression. The Investigators have demonstrated that encapsulated insulin-producing pig cells survive and function when transplanted into diabetic immunodeficient mice, but not when xenografted into immunocompetent mice. It is hypothesised that this is due to an immunological or inflammatory response by the host in response to the shedding of molecules by the encapsulated pig cells. A pre-clinical model to test the efficacy of encapsulated insulin-producing pig cells is the humanized mouse. It is hypothesized that transient administration of anti-rejection drugs will be needed to allow the survival of pig cells xenografted into these mice and normalization of BGL once diabetes has been induced. The aims of this study are: 1. To assess the nature of the host response when encapsulated insulin-producing fetal pig cells are transplanted into diabetic BALB-c mice. 2. To normalize blood glucose levels (BGL) in diabetic humanized mice transplanted with encapsulated insulin-producing fetal pig cells.Read moreRead less
The Function Of The Natural Antisense Ghrelin Receptor Gene (GHSROS) In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$493,750.00
Summary
Lung cancer is the most common cause of cancer deaths in men and women in the world and the incidence in Australia is rising with our aging population. Survival rates for lung cancer are very poor. We have discovered a new gene that is produced by lung cancer cells and may contribute to the aggressive nature of this disease. We will investigate this gene to determine if it could be a useful target for new therapies for lung cancer and it determine its utility as a biomarker for the severity of t ....Lung cancer is the most common cause of cancer deaths in men and women in the world and the incidence in Australia is rising with our aging population. Survival rates for lung cancer are very poor. We have discovered a new gene that is produced by lung cancer cells and may contribute to the aggressive nature of this disease. We will investigate this gene to determine if it could be a useful target for new therapies for lung cancer and it determine its utility as a biomarker for the severity of the disease.Read moreRead less
A Novel Approach To Streamlining The Diagnosis Of Primary Aldosteronism
Funder
National Health and Medical Research Council
Funding Amount
$269,463.00
Summary
This study will assess a new clinical test used to diagnose a potentially curable form of high blood pressure called primary aldosteronism (PA). If successful, the test will greatly streamline and simplify the diagnosis of this condition, with the potential for enormous cost savings and a markedly increased rate of diagnosis of patients with PA who can then benefit from optimal treatment and improved quality of life.
Elucidating Genetic Mechanisms Responsible For Familial Hyperaldosteronism Type II
Funder
National Health and Medical Research Council
Funding Amount
$424,812.00
Summary
Primary aldosteronism (PAL) is the commonest specifically treatable and potentially curable form of hypertension (high blood pressure), a common disease, expensive to treat, with serious morbidity and mortality. This project will use cutting edge technology to gain new knowledge concerning how genes regulate the body's production of aldosterone (salt hormone), which will help us understand how PAL develops and how common it is, and could lead to better approaches to diagnosis and treatment.
Aromatase Regulation By P53 And HIF-1alpha In Obesity And Post-menopausal Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$607,523.00
Summary
Current hormone therapy for breast cancer using inhibitors of oestrogen production results in serious side-effects including bone loss, joint pain and possibly cognitive issues. Our current work is aimed at understanding how oestrogen production is regulated with the goal of developing breast-specific inhibitors of oestrogen production to obviate these problems. In addition, this work is aimed at devising therapeutic intervention to break the linkage between obesity and breast cancer.
ARMC5 And Other Genetic Contributions In Endocrine Neoplasia
Funder
National Health and Medical Research Council
Funding Amount
$124,676.00
Summary
The adrenal glands secrete essential hormones and can enlarge or develop tumours leading to conditions including obesity, high blood pressure, diabetes, brittle bones and infections. We recently found that adrenal enlargement and tumours may be due to changes in the ARMC5 gene. We will perform genetic testing in affected patients across Australia to evaluate the roles of ARMC5 & other genes. Our goal is to better understand how these conditions develop so as to improve diagnosis and treatment.