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
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
Geldanamycin Derivatives: Novel Inhibitors Of Androgen Signalling For The Treatment Of Metastatic Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$316,320.00
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 lymph nodes and bone (ie metastatic disease). For those men with metastatic disease, reduction in testicular androgens by surgical ....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 lymph nodes and 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. However, androgen ablation is only palliative, and treatment failure is common, with less than 20% of patients surviving more than 5 years. Recent evidence suggests that the androgen receptor, which mediates the growth regulatory effects of androgens, such as testosterone, is often defective in prostate tumour cells. These altered or mutant receptors may be inappropriately activated and stimulate tumour growth which may explain why treatment fails in a subset of men with advanced prostate cancer. The major objective of our current proposal is to evaluate a novel approach for the 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. Specifically, we will examine the effectiveness of derivatives of a natural product, the antibiotic geldanamycin, to inhibit prostate tumour growth. The current studies therefore have the potential to result in improved treatment approaches for advanced prostate cancer.Read moreRead less
Microwave And Laser Energies For Percutaneous Cardiac Ablation For The Cure Of Arhythmias
Funder
National Health and Medical Research Council
Funding Amount
$331,527.00
Summary
The commonest beating disorder of the heart is atrial fibrillation (AF). Whilst it can occur at any age it is more common in the elderly with 12% Australians over 70 y.o having it. AF is the cause of a third of all strokes and increases the risk of dying from any heart disease. Ventricular tachycardia (VT) is the commonest cause of death in the year after a heart attack. Currently these beating disorders are in most cases incurable and respond poorly to medications. We have developed an operatio ....The commonest beating disorder of the heart is atrial fibrillation (AF). Whilst it can occur at any age it is more common in the elderly with 12% Australians over 70 y.o having it. AF is the cause of a third of all strokes and increases the risk of dying from any heart disease. Ventricular tachycardia (VT) is the commonest cause of death in the year after a heart attack. Currently these beating disorders are in most cases incurable and respond poorly to medications. We have developed an operation for AF which is done by open heart surgery. It has been successful at curing some patients who suffer from AF and uses radiofrequency energy. The difficulty of radiofrequency energy is that it is not suitable in a large number of cases for this operation. We are developing Laser and Microwave catheters as alternatives to RF so that the success of the operation can be improved. These new microwave and laser catheters are being designed and tested to be used primarily in a minimally invasive procedure. They would be inserted via the veins with the patient under sedation. This would allow patients to go home sooner and have a recovery period of only a few days. As well as their application in the top chamber of the heart (atrium) for AF, these new energies will be adapted for minimally invasive operations in the ventricle (lower chamber) of the heart for the treatment of ventricular tachycardia. By developing a technique such as this, cure of AFand VT will be available to many more people, helping reduce the strokes, heart failure and premature deaths from these two heart conditions.Read moreRead less
Pushing AR Toward Better Outcomes In Breast And Prostate Cancers
Funder
National Health and Medical Research Council
Funding Amount
$998,754.00
Summary
Breast and prostate cancers kill >6000 Australians each year. These cancers are strikingly similar, both driven by hormone receptors that have ‘gone bad’. Current therapies aim to eradicate the receptors. While often effective, therapeutic resistance is common and results in fatal disease. We aim to develop new, less toxic treatments that switch receptor behaviour from good to bad, without destroying them. This should improve quality of life, while preventing drug resistance and loss of lives ....Breast and prostate cancers kill >6000 Australians each year. These cancers are strikingly similar, both driven by hormone receptors that have ‘gone bad’. Current therapies aim to eradicate the receptors. While often effective, therapeutic resistance is common and results in fatal disease. We aim to develop new, less toxic treatments that switch receptor behaviour from good to bad, without destroying them. This should improve quality of life, while preventing drug resistance and loss of lives.Read moreRead less
Intraprostatic Androgen Signalling As A Target In Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$372,049.00
Summary
Male hormones (androgens) are the fuel that drives prostate cancer so reducing androgen levels is the standard treatment but cant cure the disease and causes serious side-effects throughout the body. We need to better target androgen withdrawal to prostate cancers and learn more about how it works to improve treatment. This project utilizes unique mouse models for experiments not feasible in humans to learn how androgens act and can be better targeted to cure prostate cancers.
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