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
PROTEIN TARGETS FOR THE STEROID RECEPTOR MODULATOR, CYCLOPHILIN 40
Funder
National Health and Medical Research Council
Funding Amount
$374,828.00
Summary
Steroids bind to specific receptor proteins in steroid responsive cells. These receptors are kept in a steroid-binding ready state by chaperone proteins which function to fold the receptors appropriately. The major chaperone protein is heat shock protein, hsp90. A second family of proteins called immunophilins, cooperate with hsp90 in receptor folding. These immunophilins can bind to immunosuppressant drugs, which may result in a change in receptor function. We have identified one of these immun ....Steroids bind to specific receptor proteins in steroid responsive cells. These receptors are kept in a steroid-binding ready state by chaperone proteins which function to fold the receptors appropriately. The major chaperone protein is heat shock protein, hsp90. A second family of proteins called immunophilins, cooperate with hsp90 in receptor folding. These immunophilins can bind to immunosuppressant drugs, which may result in a change in receptor function. We have identified one of these immunophilins as cyclophilin 40 ( CyP40), a protein that binds the immunosupressant drug, cyclosporin A. We have recently found that, in addition to binding to hsp90, CyP40 may bind to and regulate the function of other proteins which are important in how cells grow and die. The aims of this project are to study how CyP40 binds to hsp90 and to these other proteins and to determine the functional outcomes of these interactions.Read moreRead less
The steroid hormone aldosterone controls salt balance and hence, blood pressure. It also has been shown to have a significant role in cardiac failure. Although drugs that block the aldosterone receptor are beneficial in the treatment of heart failure, they are limited by potassium retention in the kidney. In order to develop tissue-specific blockers of the aldosterone receptor, it is necessary to identify mechanisms by which the receptor can be activated and/or blocked in these tissues.
Identification Of Regulatory Protein Interactions On The CRH Promoter
Funder
National Health and Medical Research Council
Funding Amount
$216,600.00
Summary
CRH made in the brain controls our response to stress, and when made by the placenta it controls when birth will occur. Changes to the stress response can have important implications in heart disease, cancer, obesity and many other diseases. 70% of neonatal death is a result of premature birth, and pre-term babies that survive are more likely to have intellectual handicap or cerebral palsy. This research will help us understand CRH production during stress and pregnancy.
Dual Targeting Of The Androgen Receptor For Effective And Durable Control Of Lethal Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$946,177.00
Summary
Preventing binding of androgens to the androgen receptor is the mainstay treatment for advanced prostate cancer, but resistance inevitably develops and the disease becomes lethal. We will develop a new drug that targets a part of the androgen receptor unrelated to its androgen binding function to overcome resistance to current therapy. As this drug will be effective in all stages of prostate cancer, it has high potential to improve survival outcomes for men with prostate cancer.