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 Mechanism Of Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$679,500.00
Summary
Growth hormone GH excess or deficit results in considerably shortened lifespan. While cardiovascular disease is a major element in this mortality, GH status has also been linked to kidney disease and diabetic retinopathy. Importantly, GH produced locally in breast cells and prostate cells transform s these cells, creating cancers. We aim to define how GH activates its receptor, to facilitate a GH antagonist which results from understanding how GH activates its cell surface receptor.
Characterising The Beneficial Effects Of Estrogen On The Prostate Gland
Funder
National Health and Medical Research Council
Funding Amount
$594,722.00
Summary
Prostate cancer is hormonally regulated and currently managed by androgen ablation. This application seeks to study the potential benefits of estrogen action for the treatment of prostate disease, including PCa. We will show estrogen hormone action causes prostatic cell death, targeting the stem-progenitor cells so the treated prostatic tissue does not regenerate. This project will provide pre-clinical proof of the efficacy of estrogenic compounds as a potential therapy for prostate disease.
Pathways Involved In The Insulin-like Growth Factor (IGF)-independent Actions Of IGF Binding Protein-6
Funder
National Health and Medical Research Council
Funding Amount
$550,725.00
Summary
Insulin-like growth factors (IGFs) are important proteins that regulate growth. When not regulated properly, diseases such as cancer can occur. A family of IGF binding proteins regulates IGFs. IGFBPs may inhibit IGFs and we have shown that one of them, IGFBP-6, decreases growth of some experimental cancers. As well as regulating IGFs, some IGFBPs alter cell behaviour independently of IGFs, and we found that IGFBP-6 stimulates cell movement in this way. We will now determine how this happens.
Structural And Functional Investigation Into The Cooperation Of IGF And Vitronectin-binding Receptors In Cell Migration
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Breast cancer is the most commonly diagnosed form of cancer in Australian women, accounting for 26% of diagnosed cancers and 21% of cancer deaths among women. One in fourteen Australian and one in nine women worldwide will develop breast cancer in their lifetime. Significantly, approximately one in four of those diagnosed will die from their disease. The primary factor that determines survival is early diagnosis and treatment. Indeed, the primary tumour itself rarely causes death. Rather, the di ....Breast cancer is the most commonly diagnosed form of cancer in Australian women, accounting for 26% of diagnosed cancers and 21% of cancer deaths among women. One in fourteen Australian and one in nine women worldwide will develop breast cancer in their lifetime. Significantly, approximately one in four of those diagnosed will die from their disease. The primary factor that determines survival is early diagnosis and treatment. Indeed, the primary tumour itself rarely causes death. Rather, the dissemination of tumour cells to remote sites and the establishment of secondary tumours in critical sites in the body is the major mechanism of mortality. An understanding of the processes that lead to the establishment of secondary tumour bodies and strategies to halt the spread of cancer beyond the primary site are therefore highly valuable. Two factors thought to be pivotal in breast cancer metastasis are altered interactions with the microenvironment surrounding cells and exposure to increased levels of hormones and growth factors, such as the insulin-like growth factors (IGFs). We have recently found that IGFs form complexes with a protein called vitronectin, found in the microenvironment, and these complexes can stimulate increased migration of breast cancer cells. This project will examine the interaction of IGF and VN in stimulating cell migration and in particular, aims to identify the genes involved in the enhanced cell migration. In addition we will examine how the IGF:vitronectin complexes form and how these in turn interact with receptors on the surface of the cell. The data obtained will provide critical fundamental information that is necessary to develop targeted therapies for the treatment and control of breast cancer.Read moreRead less
The Role Of Ghrelin And Growth Hormone Releasing Hormone In The Autocrine Regulation Of Prostate Cancer Cell Growth
Funder
National Health and Medical Research Council
Funding Amount
$240,990.00
Summary
Insulin-like growth factor-I (IGF-I) is an important growth factor with a major role in the growth and development of many normal and tumour cells. Its production is controlled by growth hormone (GH), released from the pituitary gland at the base of the brain. GH releasing hormone (GHRH), a hormone released from higher centres in the brain, regulates the production of GH itself and now it is recognised that a second pathway, the ghrelin-GH secretagogue receptor (GHS-R) axis is also important in ....Insulin-like growth factor-I (IGF-I) is an important growth factor with a major role in the growth and development of many normal and tumour cells. Its production is controlled by growth hormone (GH), released from the pituitary gland at the base of the brain. GH releasing hormone (GHRH), a hormone released from higher centres in the brain, regulates the production of GH itself and now it is recognised that a second pathway, the ghrelin-GH secretagogue receptor (GHS-R) axis is also important in regulating GH release. There is growing evidence that the GHRH-GH-IGF axis has a significant role in prostate cancer, but little is known about how this happens. We also have evidence that the ghrelin-GHS-R axis is involved in prostate cancer, as prostate cancer cell lines produce both ghrelin and the receptor through which it acts. Our preliminary studies show that ghrelin enhances cell growth in these cells. GHRH blocking agents (antagonists) are potential treatments for prostate cancer, as they slow the growth of prostate tumours. How they act is unclear, but they might interfere with a locally active GHRH pathway in the prostate. This study aims to explore the role of ghrelin and GHRH in prostate cancer. Since there is an increase in the use of GHRH, GH and-or IGF-I and potentially ghrelin for the treatment of a variety of medical conditions, including some in the aging male, the need for a fuller understanding of the role of this axis in prostate cancer is increasingly important. Such information will lead to a deeper understanding of the actions of ghrelin and GHRH and provide potential opportunities for design of new therapies for prostate and other GH-IGF-responsive tumours.Read moreRead less
Development Of New Anti-fibrotic Drugs For Prevention Of Diabetic Nephropathy.
Funder
National Health and Medical Research Council
Funding Amount
$133,800.00
Summary
Diabetic kidney disease is the leading cause of kidney failure in the developed world. Currently there is no treatment that reduces the excessive scarring that leads to kidney failure. This project aims to test whether a series of novel compounds that have been specifically designed to reduce scarring can prevent diabetic kidney disease.
Evaluation Of The Therapeutic Potential Of SFTI-FCQR, A Novel Kallikrein 4-specific Protease Inhibitor
Funder
National Health and Medical Research Council
Funding Amount
$167,303.00
Summary
Prostate and ovarian cancers are on the rise in Australia's ageing population. In previous work, we have studied prostate and ovarian cancer cells that we have engineered to make the protease KLK4. These cells show signs associated with aggressive tumours and in particular may have some of the changes found in cancer cells that spread from their site of origin (metastasize). In this project, we will look at a drug-like molecule that we have designed with the aim of blocking the activity of KLK4.