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.
Development Of A Specific Activin Antagonist For Therapeutic Applications
Funder
National Health and Medical Research Council
Funding Amount
$504,287.00
Summary
Activin is a key regulator of homeostasis in several organs and tissues, including ovaries, testes, liver and skin, and alterations in activin�s activity can result in fibrosis, cachexia and cancer. In this grant we propose to develop a specific activin antagonist by modifying the activin A propeptide. This novel reagent could be used to promote liver growth in severe hepatic disease and prevent fibrosis in numerous tissues.
The Nuclear Growth Hormone Receptor- Its Actions And Mechanism Of Nuclear Translocation
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourog ....We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourogenesis, and to define the physiological roles of nuclear GH receptor, we will define the transport process which carries the receptor to the nucleus and block it. We will also seek to define how the receptor in the nucleus interacts directly with DNA to inhibit programmed cell death. To carry out these projects we will use sophisticated proteomics -mass spectrometry to identify the proteins interacting with the receptor in the transport and gene activation processes. The role of candidates will be tested by preventing their expression or by direct inhibition of their action using drugs or dominant negative versions. These approaches will provide leads to new anti-cancer therapeutics, and therapies for blocking diabetic blindness and kidney failure.Read moreRead less
New insights into mammalian gene transcription - the role of parafibromin. Increasing our knowledge of fundamental gene and protein interactions is imperative as we move into an era of targetted molecular therapies to treat disease. Cancer is at the forefront of these diseases with hope of improved treatments firmly based in understanding the basic cell biology of tumours. This proposal describes research into a protein called parafibromin. We propose that parafibromin acts in major pathways res ....New insights into mammalian gene transcription - the role of parafibromin. Increasing our knowledge of fundamental gene and protein interactions is imperative as we move into an era of targetted molecular therapies to treat disease. Cancer is at the forefront of these diseases with hope of improved treatments firmly based in understanding the basic cell biology of tumours. This proposal describes research into a protein called parafibromin. We propose that parafibromin acts in major pathways responsible for how a cell manages stress by regulating levels of proteins involved in the cellular stress response. Discoveries made during the course of this research will provide knowledge of gene and protein interactions that will be important in the future to develop anti-cancer therapies. 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
Innovative Approaches for Defining the Interaction of Insulin like Growth Factor I (IGF I) with the Type 1 IGF Receptor. This study will improve our understanding of the interactions of Insulin-like Growth Factors (IGFs) with their principal receptor, the IGF-1R. A sound understanding of these interactions is essential for the development of non-peptide IGF antagonists designed for therapeutic applications. Such molecules could lead to new therapeutic approaches for diseases in which dysregul ....Innovative Approaches for Defining the Interaction of Insulin like Growth Factor I (IGF I) with the Type 1 IGF Receptor. This study will improve our understanding of the interactions of Insulin-like Growth Factors (IGFs) with their principal receptor, the IGF-1R. A sound understanding of these interactions is essential for the development of non-peptide IGF antagonists designed for therapeutic applications. Such molecules could lead to new therapeutic approaches for diseases in which dysregulation of the IGF system has been implicated including cancer, diabetes and atherosclerosis.
Since IGFs are major determinants of growth, the outcomes of this project could also lead to improvements in animal production with major benefit to primary industry. New IGF analogues developed could assist biotechnology exports.
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Molecular dynamics of steroid receptor crosstalk. This project uses state-of-the-art technology to show how steroids (for example, testosterone) affect many aspects of human life, and how these can be disrupted by chemicals and synthetic hormones. The results can be used to interpret disease, predict safety of new drugs, and to monitor risk to humans and wildlife of environmental chemicals.
The Ghrelin Axis As A Target For Prostate Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$585,497.00
Summary
Prostate cancer affects one in nine Australian men in their lifetime, and although there have been great advances in treatments, advanced prostate cancer remains incurable. Current treatments often lead to side effects which affect quality of life. We have found that the appetite hormone, ghrelin, stimulates prostate cancer cell growth and may be a useful target for prostate cancer therapy. We predict that targeting the ghrelin axis will prevent some of the side effects of other treatments that ....Prostate cancer affects one in nine Australian men in their lifetime, and although there have been great advances in treatments, advanced prostate cancer remains incurable. Current treatments often lead to side effects which affect quality of life. We have found that the appetite hormone, ghrelin, stimulates prostate cancer cell growth and may be a useful target for prostate cancer therapy. We predict that targeting the ghrelin axis will prevent some of the side effects of other treatments that reduce quality of life for patients.Read moreRead less