Inhibition Of Estrogen Signalling By Androgen Receptors: A Potential Mechanism For Suppression Of Breast Cancer Growth.
Funder
National Health and Medical Research Council
Funding Amount
$525,000.00
Summary
Breast cancer is a major health problem in Western countries including Australia, where it is the second-leading cause of cancer deaths in women. Breast cells require female sex hormones, called estrogens, for their growth and survival and consequently most current treatments for breast cancer aim to block the actions of these hormones in breast cancer cells. However there is still a large proportion of women who do not respond to these therapies or have an initial response but subsequently deve ....Breast cancer is a major health problem in Western countries including Australia, where it is the second-leading cause of cancer deaths in women. Breast cells require female sex hormones, called estrogens, for their growth and survival and consequently most current treatments for breast cancer aim to block the actions of these hormones in breast cancer cells. However there is still a large proportion of women who do not respond to these therapies or have an initial response but subsequently develop resistance. Evidence from our laboratory and others indicates that the male sex hormones, androgens, also play an important role in breast cancer. Androgens oppose the effects of estrogens in breast cancer cells, and inhibit their growth. Historically androgens were used to treat patients with advanced breast cancer, with good results, but the masculinising side effects (eg excess hair growth and acne) of these hormones led to a discontinuation of their use since the 1960s. The major objective of our current studies is to determine how androgens can stop breast cancer cells from growing by investigating the effects of the androgen receptor, which mediates the growth regulatory effects of androgens, in breast cancer cells. We believe that a better understanding of this signalling pathway could potentially lead to new treatments for breast cancer that act more specifically to inhibit cancer growth without the unpleasant side effects of androgenic drugs.Read moreRead less
Analysis Of Calcitonin Receptor Binding And Function
Funder
National Health and Medical Research Council
Funding Amount
$382,821.00
Summary
Receptors form a basic intermediary as the acceptor site for signals that are transmitted between the cells that make up our body. Modulation of receptors, therefore, forms a key target in our ability to treat disease. The largest class of receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of the entire repertoire of human genes. One group of GPCRs provide the target for small prote ....Receptors form a basic intermediary as the acceptor site for signals that are transmitted between the cells that make up our body. Modulation of receptors, therefore, forms a key target in our ability to treat disease. The largest class of receptors is the superfamily of G protein-coupled receptors (GPCRs), which transmit signals within a cell via proteins called G proteins. GPCRs form between 1 and 5% of the entire repertoire of human genes. One group of GPCRs provide the target for small protein molecules that cirulate through the body. One such circulating molecule is calcitonin, a peptide that plays an important role in maintaining circulating calcium levels in the body, which is essential for proper maintenance of the skeleton. As a consequence of this action, calcitonin is an important clinically used tool in the treatment of bone disease such as osteoporosis and Paget's disease. Due to the molecular nature of calcitonin and its receptors (and other related receptors) that have a broad, complex mechanism of interaction, we have very little definitive information on how calcitonin interfaces with its receptor to signal to target cells. The current project utilises a novel method of permanently linking calcitonin to its receptor, allowing identification of how the two components come together. Furthermore, the project will explore the functional consequence of naturally occuring genetic variation (genotype) and also examine whether the occurence of specific calcitonin receptor genotype is correlated with disease markers for osteoporosis and obesity. This information provides important fundamentals for understanding how this and related receptors work and the potential for rational design of improved theraupeutic tools.Read moreRead less
Understanding G Protein-Coupled Receptors (GPCRs): Accelerating Discovery From Concept To Clinic.
Funder
National Health and Medical Research Council
Funding Amount
$6,871,789.00
Summary
G Protein-Coupled Receptors (GPCRs) form the largest family of receptors (and thus drug targets) in living organisms. Currently, the major reason that new drugs fail to reach the clinic is lack of appropriate drug effect (approx. 30%). Thus, we need a better understanding of how GPCRs work and how this relates to disease. Our Program addresses this knowledge gap, using GPCR models that are relevant to treatment of metabolic, cardiovascular and central nervous system disease.
Investigate The Role Of PAF And CD40 Ligand In Regulating The Proinflammatory Properties Of Platelets
Funder
National Health and Medical Research Council
Funding Amount
$507,270.00
Summary
The cells of the blood play an important role in maintaining healthy blood vessels. We are interested in two types of blood cells, platelets and leukocytes, which together play a key role in vessel maintenance, by promoting blood clot formation and vessel wall repair following injury. However, while critical for normal blood vessel maintenance, these cells have also been demonstrated to contribute to disease states including atherosclerosis, thrombosis and inflammatory airway diseases. Underlyin ....The cells of the blood play an important role in maintaining healthy blood vessels. We are interested in two types of blood cells, platelets and leukocytes, which together play a key role in vessel maintenance, by promoting blood clot formation and vessel wall repair following injury. However, while critical for normal blood vessel maintenance, these cells have also been demonstrated to contribute to disease states including atherosclerosis, thrombosis and inflammatory airway diseases. Underlying the function of both blood cell types is their ability to stick (or adhere) to each other. However the way in which they coordinate this adhesion is very complex. New information from our laboratory has demonstrated that the sticky behaviour of each cell type is spatially and temporally regulated, and may involve may factors both inside and outside of the cells themselves. Our studies aim to define the key components regulating the 'stickiness' of these blood cells, in order to undertand how they contribute to maintaining healthy vessel walls, but also how their stickiness may also contribute to the promotion of diseased vessels. This information will not only increase our knowledge of the factors that regulate blood clot formation, but may also assist in the development of new therapies to prevent and-or treat vessel disease.Read moreRead less
Understanding Selective Drug Signaling At G Protein-coupled Receptors
Funder
National Health and Medical Research Council
Funding Amount
$362,206.00
Summary
The maintenance of optimum health and function living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific reciever protein at the cell surface called receptor. In one class of such receptors called G protein-coupled recept ....The maintenance of optimum health and function living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific reciever protein at the cell surface called receptor. In one class of such receptors called G protein-coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. These receptors are the most abundant type of cell surface receptors and form the targets for nearly 50% of currently used therapeutic drugs. It is, therefore, extremely important to unravel how each of these components works, and in particular to know how they work in living cells. This project utilizes state-of-the-art methodologies to examine interactions between receptors and their cognate G proteins, in living cells and in real-time. The work will answer fundamental questions about the nature of G protein-coupled receptor signaling, in particular whether new classes of drugs can be identified that more selectively activate signaling pathways or factors that attenuate signaling. This work has potential for future development of more effective therapeutic agents.Read moreRead less
Investigation Of Steroidogenesis As A Mechanism Of Castration Resistance In Human Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$419,076.00
Summary
Prostate cancer is critically dependent upon continued testosterone stimulation, even when the disease becomes resistant to existing hormonal therapies that suppress serum levels. The source of this testosterone is currently unclear. This study aims to identify the site of testosterone synthesis in patients with prostate cancer, and determine the relevance of continued testosterone signalling in patients treated with 'super castrating' hormonal therapy.
Estrogen Therapy For Castrate Resistant Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$531,690.00
Summary
Withdrawal of male hormones in men with prostate cancer is effective therapeutically because it causes cell death in most of the tumour. However the remaining cells (called castrate resistant cells), give rise to recurrent disease that inevitably kills the patient. This project aims to test if our compound will kill these cells and prevent recurrence or if it has any benefit for the patients who have incurable disease.