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
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
Proteolytic And Non-proteolytic Roles For PSA And Related Kallikrein Serine Proteases In Prostate Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$480,128.00
Summary
Prostate cancer is the most frequently occurring cancer in men in Western countries. Prostate cancer metastasis to bone and other organs is the painful end stage of this disease. The level of prostate specific antigen (PSA) in blood is often used as a marker of prostate cancer. PSA is one of 15 related enzymes in the kallikrein family of enzymes, which may be involved in breakdown of the tissue that surrounds cells in the prostate. As prostate cancer metastasis first requires spread from the pri ....Prostate cancer is the most frequently occurring cancer in men in Western countries. Prostate cancer metastasis to bone and other organs is the painful end stage of this disease. The level of prostate specific antigen (PSA) in blood is often used as a marker of prostate cancer. PSA is one of 15 related enzymes in the kallikrein family of enzymes, which may be involved in breakdown of the tissue that surrounds cells in the prostate. As prostate cancer metastasis first requires spread from the primary tumour and out of the prostate, it is possible that high production of these kallikrein enzymes by prosttae cancer cells may increase the ability of these cells to metastasise. In previous work, we have studied prostate cancer cells that we have engineered to make the kallikreins, PSA and kallikrein 4. Those cells that make PSA or kallikrein 4 are more elongated in shape and are better able to move across a porous barrier. Another important change is that these cells stop producing a protein that is usually found on the surface of these cells and is important for helping cells to stay attached to each other. When this protein is lost, these tumour cells no longer stay attached to each other and are more likely to move out of the prostate and spread into other parts of the body. The changes we observed in the cells that produce PSA and kallikrein 4 are typical of these more aggressive cancer cells. In this project, we will look at how PSA and kallikrein 4 cause the cells to undergo these changes. The majority of prostate cancer deaths arise from cancer that has spread from the primary tumour and out of the prostate capsule. This project aims to further understand the causes of prostate cancer spread and metastasis. This is a vital research priority if we are to address the mortality associated with prostate cancer metastasis and may lead to new treatment approaches for advanced metastic prostate cancer.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
Psychiatric Morbidity, Quality Of Life And Coping Styles Of Patients With Early Stage & Advanced Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$281,018.00
Summary
Prostate cancer affects thousands of men each year. Advances in treatment are continuing, but side-effects frequently create disruptions to daily living. If the quality of care for prostate cancer patients is to be further improved, there is much to be learned about the psychosocial impact of the disease and its treatment across its different phases. There has not been a systematic prospective study of psychosocial adjustment in men with prostate cancer. In this study, we longitudinally follow t ....Prostate cancer affects thousands of men each year. Advances in treatment are continuing, but side-effects frequently create disruptions to daily living. If the quality of care for prostate cancer patients is to be further improved, there is much to be learned about the psychosocial impact of the disease and its treatment across its different phases. There has not been a systematic prospective study of psychosocial adjustment in men with prostate cancer. In this study, we longitudinally follow two separate groups of men with prostate cancer, those with early disease and those with advanced illness. We focus on the particular side-effects of urinary incontinence, impotence and bowel symptoms and the potential these have to affect the patient's sense of wellbeing. We use a standardised interview and questionnaires to assess for the presence of psychiatric disorders and psychological problems, overall quality of life and coping styles in these men. We seek to recognise the predictors of men who may have coping problems. A statistical approach termed pathway analysis will help us understand the relative contributions of different factors associated with these problems. The outcome of this systematic, longitudinal study will be a body of knowledge concerning risk factors for poorer psychosocial adjustment and optimum coping strategies for managing the impact of prostate cancer and its treatment, thereby empowering a range of targeted interventions to be developed to enhance the wellbeing and quality of life of these men.Read moreRead less
Defining Stromal-Cancer Cell Interactions For Xenografting Human Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$559,635.00
Summary
Prostate Cancer research continues to be hindered by a lack of laboratory models to understand disease progression and design new drugs to cure the disease. In this study, we propose to use a new and reliable method of growing human prostate cancer tissue in mice. Using this model, we will investigate the role of hormone signalling and cellular communication in prostate cancer that may lead to new therapies for men diagnosed with organ-confined disease.
Does Palliative Chemotherapy Improve Symptoms In Women With Recurrent Ovarian Cancer?
Funder
National Health and Medical Research Council
Funding Amount
$521,878.00
Summary
This is a study in women who have relapsed ovarian cancer, and who are about to start further chemotherapy. Subjects will answer questions about their quality of life in order to measure any improvement in their symptoms and well being in response to palliative treatment. The study will relate subjects own reporting of improvement with their actual clinical response. The aim of this study is to develop an optimal palliative chemotherapy regime for use in future clinical trials.
Prognostic Importance Of Androgen Receptors In Epithelium And Stroma In Early Stage Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$348,750.00
Summary
The use of serum prostate specific antigen (PSA) to screen asymptomatic men for prostate cancer has reduced the stage of disease at diagnosis. The majority of tumours are now small and potentially organ-confined. The use of nomograms, algorithms based on preoperative clinical features of these patients (serum PSA level, Gleason grade, clinical stage) has facilitated this process, but is imperfect as 20-30% of patients experience disease relapse within 5-7 years. Tumours with similar preoperative ....The use of serum prostate specific antigen (PSA) to screen asymptomatic men for prostate cancer has reduced the stage of disease at diagnosis. The majority of tumours are now small and potentially organ-confined. The use of nomograms, algorithms based on preoperative clinical features of these patients (serum PSA level, Gleason grade, clinical stage) has facilitated this process, but is imperfect as 20-30% of patients experience disease relapse within 5-7 years. Tumours with similar preoperative clinical features have markedly different outcomes, reinforcing the inadequacy of current approaches to determining whether or not an individual patient has organ-confined disease. A new approach is to incorporate into the standard diagnostic nomograms, biological features from preoperative core biopsy linked to the process of disease relapse, and which independently predict patient outcome risk group. Our preliminary studies using a small hypothesis-generating cohort of patients with early stage prostate cancer determined that elevated levels of androgen receptors (AR) in malignant epithelial cells and reduced levels of AR in peritumoral stromal cells independently predict disease relapse after surgery. In this project, AR measurements will be analysed in independent cohorts of patients derived from two Australian institutions to determine whether the predictive value is maintained across multi-Institutional cohorts. Selected androgen-regulated markers of tumour growth and spread (proliferative, apoptotic, metastatic) will be examined in microarrayed postoperative tissue samples. The postoperative markers will be examined for independence of prediction of relapse. Independent markers will be examined for ability to increase predictive efficacy in standard diagnostic nomograms. Levels of the two markers with greatest predictive value will be measured in preoperative core biopsies and tested for predictive ability as a prelude to clinical practice.Read moreRead less
The Role Of A Protease Activated Receptor System In Prostate Cancer Bone Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$582,204.00
Summary
Prostate cancer is one of the most significant health issues for men. This disease occurs because certain proteins start to function abnormally. Our focus is on a protein called PAR2, present on the surface of prostate cancer cells and bone cells, which we propose helps cancer cells to spread to bone. In our project, we aim to understand how this happens so that we can develop ways to block prostate cancer metastasis to bone.
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.