Characterisation Of Alterations In The Androgen Signalling Axis That Contribute To Treatment Failure In Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$559,157.00
Summary
Prostate cancer is a major health problem in Western Countries including Australia, where it is the most common newly diagnosed invasive cancer and the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis of prostate cancer, many men are still diagnosed with disease that already has or will spread to other sites such as bone (ie metastatic disease). For those men with metastatic disease, reduction in testicular androgens by surgical or medical mean ....Prostate cancer is a major health problem in Western Countries including Australia, where it is the most common newly diagnosed invasive cancer and the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis of prostate cancer, many men are still diagnosed with disease that already has or will spread to other sites such as bone (ie metastatic disease). For those men with metastatic disease, reduction in testicular androgens by surgical or medical means (ie androgen ablation) is the only effective treatment option available. While androgen ablation is initially effective, treatment failure is common, resulting in a very poor overall survival rate. Evidence from our studies and others suggest that, the androgen receptor, which mediates the growth regulatory effects of androgens is often defective in prostate tumour cells. These altered or mutant receptors are activated inappropriately by other sex hormones such as estradiol and even agents used in the treatment of prostate cancer whereas the normal receptor is activated only by testicular androgens. This mechanism may explain why treatment fails in a subset of men with advanced prostate cancer. The major objective of our current studies is to define how these mutant androgen receptors cause treatment failure and facilitate prostate tumour growth. In addition, the current studies will evaluate a novel approach to treatment of prostate cancer which, based upon our preliminary results, has the potential to be effective even if alterations are present in the androgen receptor. The current studies therefore will provide a better understanding of factors controlling the growth of prostate tumours, and develop improved treatment approaches for advanced prostate cancer.Read moreRead less
Androgen Receptor Signalling And Progression Of Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$462,750.00
Summary
Prostate cancer is a major health problem in Australia, being the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis and treatment of prostate cancer, there are no effective treatments for advanced (metastatic) disease that has spread to other parts of the body. Currently, the only therapy for advanced disease involves the reduction in circulating androgens such as testosterone by surgical or medical castration, i.e. androgen ablation. Because pr ....Prostate cancer is a major health problem in Australia, being the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis and treatment of prostate cancer, there are no effective treatments for advanced (metastatic) disease that has spread to other parts of the body. Currently, the only therapy for advanced disease involves the reduction in circulating androgens such as testosterone by surgical or medical castration, i.e. androgen ablation. Because prostate cells are dependent on testicular androgens for their survival, surgical or medical castration results in an initial tumour regression. However, tumours inevitably develop resistance to current forms of androgen ablation therapy. Inappropriate activation of androgen signalling by non-testicular androgens or other agents may stimulate tumour growth following androgen ablation. In this study, we aim to identify and characterise determinants of the specificity and sensitivity of activation of the androgen receptor, which is the primary mediator of androgen action. Current androgen ablation treatments for prostate cancer only target the availability of androgenic ligands. We propose that it is also necessary to target the androgen receptor itself, because it can be activated by ligands other than testicular androgens. Therefore, we will also evaluate a panel ofagents that target different aspects of the androgen signalling axis, combined with androgen ablation using a cyclical approach to prevent or delay disease progression.Read moreRead less
The Role Of Androgens In Osteoblast Development And Bone Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$64,631.00
Summary
Male hormones are essential for the growth and maintenance of bone in men, but exactly how and when they act on the bone forming cells is unclear. We aim to find out what happens when the target for male hormones (receptor) is removed in the bone forming cells at different stages of their development. This project will increase our understanding of how male hormones regulate bone formation and may assist in the design of new therapies for osteoporosis.
The Clinicial Centre Of Research Excellence At The Jean Hailes Foundation: For The Study Of Women's Health
Funder
National Health and Medical Research Council
Funding Amount
$2,000,000.00
Summary
The major health issues affecting women from the mid-reproductive years include depression, disorders of mood and sexual function, and breast cancer, with cardiovascular disease, osteoporosis, and osteoarthritis becoming increasingly prevalent with age. Linking each of these are their known or probable causal associations with oestrogens and androgens. This Centre will provide an opportunity for comprehensive and multidisciplinary research into the role of oestrogens and androgens in these disor ....The major health issues affecting women from the mid-reproductive years include depression, disorders of mood and sexual function, and breast cancer, with cardiovascular disease, osteoporosis, and osteoarthritis becoming increasingly prevalent with age. Linking each of these are their known or probable causal associations with oestrogens and androgens. This Centre will provide an opportunity for comprehensive and multidisciplinary research into the role of oestrogens and androgens in these disorders.Read moreRead less
Regulation Of Growth Hormone Action By Sex Steroids: Metabolic Implications For Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$353,250.00
Summary
Fitness and health is determined by body composition, the amount of fat and lean tissue in the body. Obesity increases the risk of diabetes, blood pressure and heart attacks, while muscle wasting reduces strength and fitness. Body composition is controlled by hormones such as growth hormone (GH) which reduces body fat by stimulating its metabolism (burning) and increases lean tissue by stimulating protein synthesis. These metabolic actions of GH are exerted through the liver. This proposal seeks ....Fitness and health is determined by body composition, the amount of fat and lean tissue in the body. Obesity increases the risk of diabetes, blood pressure and heart attacks, while muscle wasting reduces strength and fitness. Body composition is controlled by hormones such as growth hormone (GH) which reduces body fat by stimulating its metabolism (burning) and increases lean tissue by stimulating protein synthesis. These metabolic actions of GH are exerted through the liver. This proposal seeks to understand how sex hormones control the amount of body fat and muscle in women and men. Based on previous research in our laboratory, we propose that sex hormones control the action of growth hormone on the liver. We will test the hypothesis that oestrogens impair the ability of the liver to burn fat and build protein in response to GH while male hormones have the opposite effect. The effect of oestrogen occurs only when oestrogen is taken as a tablet because the liver is exposed to high concentrations of this hormone after gut absorption. It causes postmenopausal women to gain fat and lose muscle. Apart from oestrogens, there are many other compounds with oestrogen-like activities such as phytooestrogens (oestrogens found in plants) and SERMs (used for treating osteoporosis). Their effect on the liver and body composition are unknown but important because of their widespread use in the community. The significance of these studies relate to optimising the benefits of oestrogen compounds by defining their metabolic effects on the liver. In men, understanding how male hormones work as anabolic agents may lead to ways of treating protein muscle wasting.Read moreRead less