Role Of Cyclin E2 In Hormone-responsive Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$328,194.00
Summary
The female hormone estrogen stimulates the growth of breast cancers by promoting cell reproduction. We have found that cyclin E2, which is part of the machinery that controls cell reproduction, responds to estrogen. Since abnormally high levels of cyclin E2 are linked with earlier relapse in breast cancer, we wish to understand what role it plays in estrogen action and in breast cancer, how its levels are controlled, and whether too much cyclin E2 interferes with drugs that block estrogen action
Prevention Of Late Breast Cancer (BC) Events In Postmenopausal Women With Endocrine Responsive BC.
Funder
National Health and Medical Research Council
Funding Amount
$4,687,599.00
Summary
This proposal is from Australia's national breast cancer (BC) trials group, the ANZ BCTG, for a new phase III, multi-centre clinical trial evaluating whether much later endocrine therapy with an aromatase inhibitor can prevent BC recurrence in postmenopausal women who have: had hormone sensitive BC at least 6 years ago; were treated by Tamoxifen more than 1 year ago; and, are currently disease free. Subjects will randomly receive letrozole or placebo as a daily tablet for five years.
Exploring A New Way To Overcoming Endocrine Resistance In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$441,764.00
Summary
Despite significant improvements in long-term outcome with the use of endocrine therapy (such as tamoxifen and letrozole), breast cancer remains the most common cause of cancer-related death amongst Australian women. A major clinical problem limiting the effectiveness of endocrine therapy is tumour resistance, either intrinsic or acquired. Indeed, about half of patients immediately fail to respond to the treatment, while in the initially responding patients the tumours ultimately progress to res ....Despite significant improvements in long-term outcome with the use of endocrine therapy (such as tamoxifen and letrozole), breast cancer remains the most common cause of cancer-related death amongst Australian women. A major clinical problem limiting the effectiveness of endocrine therapy is tumour resistance, either intrinsic or acquired. Indeed, about half of patients immediately fail to respond to the treatment, while in the initially responding patients the tumours ultimately progress to resistance to the drug leading to the disease relapse. Therefore, it is imperative to better understand the mechanisms responsible for the resistance and to explore new strategies that overcome this clinical problem in order to prolong the overall survival of patients with breast cancer. Our recent work have shown that a recently-identified enzyme, termed sphingosine kinase, plays an important role in promoting breast cancer cell growth. We also found that cells that have a high level of the enzyme had bad outcomes in response to anti-estrogen drug, tamoxifen. Thus this project seeks to identify the role of this enzyme in contributing towards drug resistance, and test if inhibition of this enzyme could improve and-or restore the drug response in breast cancer. It will ultimately pave a new way to overcoming the drug resistance for improving the treatment and prevention of breast cancer.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.
Validating A New Model For Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflam ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.Read moreRead less
Enrichment, Differentiation And Functional Analysis Of Growth Hormone Progenitor Cells From The Adult Mouse Pituitary
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
Many important bodily functions including growth, metabolism, onset of puberty, fertility, lactation and the ability to cope with stress are controlled by hormones secreted by the pituitary gland. Consequently, insufficient hormone production by the pituitary gland (hypopituitarism) results in life-threatening conditions which are a significant clinical problem. Growth Hormone (GH) deficiency is the most common form of pituitary hormone deficiency, affecting 1:3,500 individuals. Currently, GH de ....Many important bodily functions including growth, metabolism, onset of puberty, fertility, lactation and the ability to cope with stress are controlled by hormones secreted by the pituitary gland. Consequently, insufficient hormone production by the pituitary gland (hypopituitarism) results in life-threatening conditions which are a significant clinical problem. Growth Hormone (GH) deficiency is the most common form of pituitary hormone deficiency, affecting 1:3,500 individuals. Currently, GH deficiency is treated by daily injections of growth hormone at a cost of $30,000 to $50,000 per patient per annum. However, even with daily injections and despite the cost, it is difficult to mimic the naturally fluctuating hormone levels in the body, resulting in incomplete growth rescue. Long term injections also have severe side effects that can lead to cardiovascular problems, abnormal bone density, diabetes and cancers of various types. To overcome the disadvantages of hormone therapy we are investigating a new cell replacement therapy to treat GH deficiency. This approach requires knowledge about the mechanism by which GH-secreting cells are generated and maintained in the adult pituitary. For the first time, we have isolated a type of progenitor (unspecialised) cell from adult mouse pituitary that is capable of dividing and generating GH-secreting cells. Our current research aims to further purify these cells and to show that they are capable of secreting GH in response to biologically relevant signals. In addition, we will test whether these cells can grow and develop into functional cells when introduced into mice. In particular, we will test whether the progenitor cells can rescue dwarfism using a mouse model of GH deficiency. This pioneering study will provide the first insight into the possibility of cell therapy for the pituitary, and may ultimately lead to the development of better therapies for patients with GH deficiency.Read moreRead less
A Randomised Phase III Trial Of Anastrozole For Breast Cancer Prevention In Postmenopausal Women At High Risk.
Funder
National Health and Medical Research Council
Funding Amount
$1,593,125.00
Summary
Each year over 10,000 new cases of breast cancer are diagnosed in Australia and over 2500 women die. This project (IBIS 2) is designed to continue the work started by the IBIS 1 prevention trial in determining whether a chemopreventive strategy towards breast cancer is beneficial. IBIS 1 investigated the use of tamoxifen as a preventative agent for women with moderate to increased risk of developing breast cancer and was found to prevent 48% of oestrogen receptor positive breast cancers. IBIS 2 ....Each year over 10,000 new cases of breast cancer are diagnosed in Australia and over 2500 women die. This project (IBIS 2) is designed to continue the work started by the IBIS 1 prevention trial in determining whether a chemopreventive strategy towards breast cancer is beneficial. IBIS 1 investigated the use of tamoxifen as a preventative agent for women with moderate to increased risk of developing breast cancer and was found to prevent 48% of oestrogen receptor positive breast cancers. IBIS 2 investigates anastrozole (Arimidex) as a preventative agent for women with moderate to increased risk of developing breast cancer. It is a multi-centre, randomised, double blind control trial which has the potential to benefit many millions of women worldwide. Anastrozole is an aromatase inhibitor (AI). AIs are a class of endocrine drug which have been shown to be at least as effective as tamoxifen but without the serious side effects seen with tamoxifen. Anastrozole has been shown to be 60% better than tamoxifen in preventing a second breast cancer in women already diagnosed with breast cancer. Women who participate in this study will be postmenopausal with a relative risk of at least two-fold of developing breast cancer. They will be randomised to receive either anastrozole or placebo as a daily tablet, and neither the woman nor her treating clinician will know which treatment has been allocated (double blind study). To investigate whether anastrozole effects bone density, a baseline bone density scan will be measured prior to study entry. This sub-study will investigate bone density in greater detail and the potential role of bone preserving treatment (bisphosphonate). The primary endpoint for the IBIS 2 study is the development of histologically confirmed breast cancer, invasive or non-invasive.Read moreRead less
IBIS II: A Randomised Phase III Trial Of Anastrozole For Breast Cancer Prevention In Postmenopausal Women At High Risk.
Funder
National Health and Medical Research Council
Funding Amount
$1,732,559.00
Summary
The IBIS II trial builds on the successful IBIS 1 breast cancer (BC) prevention trial in determining whether a chemopreventive strategy towards BC is beneficial. Women who are postmenopausal with an increased risk of BC are randomised to receive either anastrozole (an aromatase inhibitor) or placebo as a daily tablet. Neither the woman nor her clinician know which treatment has been allocated (double blind study). IBIS 2 has the potential to benefit many higher risk women worldwide.
Xenotransplantation Of Encapsulated Insulin-producing Pig Cells
Funder
National Health and Medical Research Council
Funding Amount
$763,316.00
Summary
The ideal treatment for insulin-dependent diabetes is the replacement of insulin-producing cells. Currently, this is carried out using a whole pancreas or experimentally with cells isolated from the pancreas of donor humans. Despite the success of these procedures, demand for human organs far exceeds supply, thus driving the search for suitable alternatives. Pigs are physiologically similar to humans, and insulin-producing cells can be easily isolated from the fetal pig pancreas as islet-like ce ....The ideal treatment for insulin-dependent diabetes is the replacement of insulin-producing cells. Currently, this is carried out using a whole pancreas or experimentally with cells isolated from the pancreas of donor humans. Despite the success of these procedures, demand for human organs far exceeds supply, thus driving the search for suitable alternatives. Pigs are physiologically similar to humans, and insulin-producing cells can be easily isolated from the fetal pig pancreas as islet-like cell clusters; 8% of the cells in the cluster produce insulin and the remaining cells develop this capability after transplantation. Transplantation requires chronic immunosuppression with drugs which increase the risk of infection and cancer. To many people with diabetes, the side effects will be greater than the potential benefit. Placing cells inside microcapsules made of a biologically inert material may prevent graft rejection without chronic immunosuppression. The Investigators have demonstrated that encapsulated insulin-producing pig cells survive and function when transplanted into diabetic immunodeficient mice, but not when xenografted into immunocompetent mice. It is hypothesised that this is due to an immunological or inflammatory response by the host in response to the shedding of molecules by the encapsulated pig cells. A pre-clinical model to test the efficacy of encapsulated insulin-producing pig cells is the humanized mouse. It is hypothesized that transient administration of anti-rejection drugs will be needed to allow the survival of pig cells xenografted into these mice and normalization of BGL once diabetes has been induced. The aims of this study are: 1. To assess the nature of the host response when encapsulated insulin-producing fetal pig cells are transplanted into diabetic BALB-c mice. 2. To normalize blood glucose levels (BGL) in diabetic humanized mice transplanted with encapsulated insulin-producing fetal pig cells.Read moreRead less
Optimal Duration Of Neoadjuvant Androgen Deprivation Therapy In Localised Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$275,000.00
Summary
Each year approximately 8000 men in Australia and New Zealand develop prostate cancer which has not spread widely and which is amenable to attempted cure by surgery or radiation. Prostate cancer depends for its growth on the male hormone, testosterone, which circulates in the blood. As a result treatment which reduces testosterone level ('androgen deprivation' [AD] therapy) can produce shrinkage of prostate cancer. In fact AD has caused temporary but valued relief to millions of men with cancer ....Each year approximately 8000 men in Australia and New Zealand develop prostate cancer which has not spread widely and which is amenable to attempted cure by surgery or radiation. Prostate cancer depends for its growth on the male hormone, testosterone, which circulates in the blood. As a result treatment which reduces testosterone level ('androgen deprivation' [AD] therapy) can produce shrinkage of prostate cancer. In fact AD has caused temporary but valued relief to millions of men with cancer of the prostate that has spread throughout the body for the last five decades, worldwide. It remains uncertain however whether AD administered before surgery or radiation will benefit any of the 8000 men each year who develop localised cancer by shrinking the cancer first. In 1996 a trial involving 800 men across Australia and New Zealand commenced under the auspices of the Trans-Tasman Radiation Oncology Group (TROG) to answer the questions: 1 - Does either 3 or 6 months AD prior to radiotherapy reduce the chances of recurrence of the cancer after radiotherapy? 2 - Does such therapy reduce the volume of tissue requiring radiotherapy and hence the chances of long term side effects after radiotherapy? This grant will support collection of follow-up information from the trial and hence answers to the questions asked.Read moreRead less