Identifying Mechanisms Of Resistance To Novel Hormonal Agents In Patients With Castrate-resistant Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$420,004.00
Summary
I am a medical oncologist focused on prostate cancer, a disease which kills over 3000 Australian men every year. Recent studies have shown that new hormone treatments help men with advanced prostate cancer live longer. Unfortunately, while these drugs are effective when first started, prostate cancers eventually become resistant to them and start growing again. By looking at why these drugs stop working, I hope to find better treatments for Australian men with advanced prostate cancer.
Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility t ....Steroid hormones, such as estrogen and androgens, act in the body by locking onto a family of proteins (nuclear receptors) that bind directly to the DNA to regulate genes. The mechanisms underlying this process are complex and involve recruitment of additional molecules or coactivators to improve efficiency. Recently a novel coactivator was identified, termed SRA, which exerts its effects as an RNA, rather than as a protein. SRA is aberrantly expressed in breast cancer, raising the possibility that it plays an important role in breast cancer cell proliferation. To better understand how estrogen signals in breast cancer and identify proteins that bind to SRA in cancer cells, we established a collaboration with the O'Malley group at Baylor College of Medicine in Texas (who discovered SRA). We have identified several novel SRA-binding proteins, each of which plays an important role to regulate estrogen and androgen action. Up to this point, we have used a model that has enabled proof of principle studies in the same cancer cells from which SRA was discovered (non-breast or prostate cancer). However, we now need to carefully study the role of these proteins in cancer cells relevant to breast and prostate cancer. Thus, we plan to investigate how these proteins interact with SRA, how they influence nuclear receptor activity and breast and prostate cancer cell proliferation, examine their role in activating other pathways of cell growth in cancer cells, assay the levels of each protein in a series of human breast cancer specimens and solve the physcial 3-D structure of these proteins complexed to the SRA RNA. This work will provide novel insight into several key areas of hormone action in breast and prostate cancer. We hope to identify new markers that can be used for improved diagnosis and for prognosis, and provide structural information for the development of novel therapeutics.Read moreRead less
Profiling Circulating DNA And RNA To Identify Mechanisms Of Therapeutic Resistance And Response In Metastatic Castration-resistant Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$482,590.00
Summary
Enzalutamide is a powerful hormone treatment that improves survival for men with advanced prostate cancer. Unfortunately, all prostate cancers eventually become resistant to enzalutamide and not all men initially respond to treatment. I will look for blood markers that predict which men benefit from enzalutamide treatment and try to understand how resistance to enzalutamide occurs. This may lead to more effective use of enzalutamide resulting in better outcomes in advanced prostate cancer.
Obesity is an important cause of disease, including liver disease. Obesity-associated liver disease occurs when the liver becoming resistance to the effects of insulin, the hormone that controls blood sugar (glucose). In muscle and fat, insulin causes glucose to be taken into the tissues and stored. Glucose is made in the liver and the actions of insulin here are to turn off the release of glucose into the circulation and increase uptake and storage of glucose. Insulin resistance occurs in a num ....Obesity is an important cause of disease, including liver disease. Obesity-associated liver disease occurs when the liver becoming resistance to the effects of insulin, the hormone that controls blood sugar (glucose). In muscle and fat, insulin causes glucose to be taken into the tissues and stored. Glucose is made in the liver and the actions of insulin here are to turn off the release of glucose into the circulation and increase uptake and storage of glucose. Insulin resistance occurs in a number of situations but the most important of these is obesity, particularly when there is accumulation of fat inside the abdominal cavity. Although the liver has a central role in co-ordinating the bodies response to insulin, the mechanisms of insulin resistance in human liver are unknown. One prominent hypothesis is that fat molecules released by intra-abdominal fat deposits are responsible. Intra-abdominal fat stores are important because fatty acids from these deposits can travel directly to the liver with the blood supply from the gut. However the precise effects of these on insulin action in the liver are unknown. Fat tissue is actively involved in the regulation of metabolism and releases a number of regulatory proteins. One of these, adiponectin, appears to have an important role in improving insulin sensitivity in the liver. The production of adiponectin decreases as obesity increases, providing another link between obesity and insulin resistance in the liver. This project will examine insulin action and the signalling molecules responsible for this in human liver tissue. The project aims to determine the effect of obesity, particularly intra-abdominal fat deposits, on insulin responses in liver tissue. The studies also aim to confirm (or otherwise) the role of free fatty acids and adiponectin on insulin action in human liver. The data from these studies will contribute to our understanding of insulin resistance and obesity-related liver disease.Read moreRead less
Hormone Transport By Alpha-2-Macroglobulin: Novel Roles In Regulating Hormone Activity
Funder
National Health and Medical Research Council
Funding Amount
$602,857.00
Summary
Alpha-2-macroglobulin is a large protein in the blood known to bind and transport numerous hormones in the circulation. Our previous studies published in BLOOD (2009) and JBC (2013) have discovered an important role for this molecule in the transport and regulation of a peptide hormone. The studies proposed in this application have important implications for understanding new roles of alpha-2-macroglobulin in hormone binding and regulating the activity of hormones in disease states.
Adiponectin - Multimerization, Secretion And Action
Funder
National Health and Medical Research Council
Funding Amount
$478,844.00
Summary
Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose levels and acts to prevent damage to blood vessels associated with heart disease and stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and heart disease, and in animals with these conditions, additional adiponectin is of benefit. It has recently been recognised that adiponectin is produced in different forms - a low weight form made up of a small number of adiponectin molecules ....Adiponectin is a hormone produced by fat tissue. It functions to control blood glucose levels and acts to prevent damage to blood vessels associated with heart disease and stroke. Adiponectin levels in the blood are low in subjects with obesity, diabetes and heart disease, and in animals with these conditions, additional adiponectin is of benefit. It has recently been recognised that adiponectin is produced in different forms - a low weight form made up of a small number of adiponectin molecules and a higher weight form (HMW adiponectin) made up of large numbers of adiponectin molecules complexed together. We and others have shown that the HMW adiponectin is particularly beneficial. This projects aims to understand the processes regulating the production of differing types of adiponectin by fat cells. It will also examine how the different types of adiponectin have their effects in different tissues such as liver and muscle. The information gained will increase our understanding of how illnesses such as diabetes are associated with obesity. It may also lead to the development of treatments aimed at increasing adiponectin levels - particulalry HMW adiponectin - which may be of benefit in patients with diabetes and cardiovascular disease.Read moreRead less