The applicant's research is aimed at delineating the molecular mechanisms of action of steroid hormones in the pathogenesis of breast and prostate cancer with the goal of developing new diagnostic, prognostic and therapeutic response parameters of clinica
Tailored Treatments For Premenopausal Patients With Endocrine Responsive Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$257,250.00
Summary
For women under 50 years with hormone receptor positive (ER+) breast cancer, adjuvant treatment with chemotherapy, tamoxifen and ovarian ablation are each effective and reduce recurrence. Combining two treatments is more effective than one, although it is uncertain if combining three provides extra benefit. Ovarian ablation by surgery or radiation is permanent, but reversible ovarian suppression by injections is now available. Three international trials called SOFT, TEXT and PERCHE have been des ....For women under 50 years with hormone receptor positive (ER+) breast cancer, adjuvant treatment with chemotherapy, tamoxifen and ovarian ablation are each effective and reduce recurrence. Combining two treatments is more effective than one, although it is uncertain if combining three provides extra benefit. Ovarian ablation by surgery or radiation is permanent, but reversible ovarian suppression by injections is now available. Three international trials called SOFT, TEXT and PERCHE have been designed for adjuvant therapy of premenopausal women with ER+ breast cancer. These trials take into account regional-country variations in medical practice and different patient choices in this setting. SOFT is for very young women and tests the benefit of adding ovarian suppression in a woman who has received chemotherapy, with tamoxifen planned, but who has not gone into menopause after chemotherapy. The trial also tests if substituting a newer drug called exemestane for tamoxifen, combined with ovarian function suppression is more effective. TEXT is for women who would ordinarily be treated with ovarian suppression plus tamoxifen. The TEXT trial also tests substitution of exemestane for tamoxifen. Exemestane is an aromatase inhibitor. Aromatase inhibitors lower oestrogen levels, but only work if the ovaries are inactive. Recent trials in post menopausal women show aromatase inhibitors are more effective than tamoxifen, and we aim to replicate that improvement in younger women by combining exemestane with ovarian suppression. PERCHE is for women in whom the benefit of chemotherapy is uncertain, for example those with limited or no spread to lymph nodes. All women receive combined endocrine treatment with ovarian suppression plus tamoxifen, and are randomised to receive in addition, either chemotherapy or no chemotherapy, to see if results differ.Read moreRead less
A Clinical Trial To Determine The Optimal Timing Of Androgen Deprivation In Relapsed Or Non-curable Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$627,600.00
Summary
The aim of the study is to clarify when is the optimal time to start hormone treatment for men with certain stages of prostate cancer. It has long been known that testosterone removal impedes prostate cancer growth, although not permanently. The removal of testosterone, however, has side effects , including loss of libido, hot flushes, weight gain, and in the longer term osteoporosis, loss of muscle bulk and mental changes such as loss of memory. Any benefit to be gained for a patient must there ....The aim of the study is to clarify when is the optimal time to start hormone treatment for men with certain stages of prostate cancer. It has long been known that testosterone removal impedes prostate cancer growth, although not permanently. The removal of testosterone, however, has side effects , including loss of libido, hot flushes, weight gain, and in the longer term osteoporosis, loss of muscle bulk and mental changes such as loss of memory. Any benefit to be gained for a patient must therefore be weighed against these side effects. This is particularly relevant in situations in which cure is not possible, when the aim of treatment should be to manage symptoms (either by preventing or delaying them or treating them as they arise). There are two situations in which a man may be diagnosed as having active prostate cancer but be without symptoms requiring immediate treatment. The first is after the failure of curative treatment, shown by the presence of prostate specific antigen (PSA) in the blood, but without any other evidence of prostate cancer. The second is a man newly diagnosed with asymptomatic prostate cancer, but with other reasons (such as heart disease) which make an attempt at cure inappropriate. We do not know in either case whether or not men live longer if treatment is started immediately, or whether it is reasonable to wait until symptoms develop, thus potentially postponing the side effects of treatment. The trial will therefore include these two groups of men. Half the men will be randomised to receive immediate treatment, and half to treatment starting when symptoms develop, or when there is evidence of progressive disease. The main endpoint is overall survival, balanced against quality of life and side effects from the disease and treatment. The hypothesis is that early treatment will improve survival with acceptable effects on quality of life.Read moreRead less
APC Mutation And The Initiation Of Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$606,267.00
Summary
Colorectal (or bowel) cancer is a major health problem in Australia. At present it is the most common cancer, approximately 1 in 21 Australians will develop the disease in his-her lifetime. The risk of bowel cancer increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for advanced colorectal cancer are not very effective. Mortality from colorectal cancer is high, being second only to lung cancer as the leading cause of cancer death in Australia. ....Colorectal (or bowel) cancer is a major health problem in Australia. At present it is the most common cancer, approximately 1 in 21 Australians will develop the disease in his-her lifetime. The risk of bowel cancer increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for advanced colorectal cancer are not very effective. Mortality from colorectal cancer is high, being second only to lung cancer as the leading cause of cancer death in Australia. The development of colorectal cancer is affected by both genetic and environmental factors. Colorectal cancer progresses through a number of distinct pathological stages. This is thought to be the result of the progressive aquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations in a gene known as APC are associated with the very early stages of tumour formation in at least 80% of colorectal tumours. Our research is aimed at understanding how alterations in APC influence the behaviour and growth of colonic cells. We have developed a novel system where normal mouse colon can be maintained and grown for up to 2 weeks in a Petri dish. Alterations in the APC gene and other colon cancer genes will be introduced into the normal epithelial cell lining and the effects on the growth and behaviour of the cells in organ culture will be analysed. Our hypothesis is that changes in the APC gene affects the way cells migrate, divide and move. This work should improve our knowledge of the cellular changes that occur during tumour initiation in the bowel and aims to contribute to the design of new therapies for early intervention in colon cancer.Read moreRead less
Biomarkers And EGFR Inhibitor Treatment Of Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$286,328.00
Summary
Non-Small Cell Lung Cancer (NSCLC) remains the most frequent cause of cancer death in the Australian population. This laboratory research will involve researchers across a number of centres in Australia. The research is focused on the effects of a new targeted cancer drug called cetuximab. The Epidermal Growth Factor Receptor (EGFR) pathway is an important cause of NSCLC in many patients, and this is blocked by cetuximab. The advent of new targeted cancer therapies, which block specific cancer p ....Non-Small Cell Lung Cancer (NSCLC) remains the most frequent cause of cancer death in the Australian population. This laboratory research will involve researchers across a number of centres in Australia. The research is focused on the effects of a new targeted cancer drug called cetuximab. The Epidermal Growth Factor Receptor (EGFR) pathway is an important cause of NSCLC in many patients, and this is blocked by cetuximab. The advent of new targeted cancer therapies, which block specific cancer pathways in the cell, has highlighted the need for detailed knowledge about how these therapies work at the molecular level, so that we can make best use of them. The laboratory studies will be on tissues taken from patients with NSCLC who are receiving chemotherapy then going on to surgery to have the cancers removed. Tumour samples will be taken prior to treatment, and then the surgical resection will also be analysed. Sequential blood samples will also be taken. Prior to surgery, patients will receive a 9 week course of chemotherapy with cisplatin and docetaxel to shrink the cancer. In addition, some patients will be randomised to receive cetuximab along with chemotherapy. In the laboratory, we will investigate whether various measures of activation of the EGFR pathway in the cancer and in blood predict for response to cetuximab. We will also investigate how the changes in tumour with cetuximab treatment differ from tumours not treated with the drug. We will be examining the genes and proteins of EGFR and those of a number of related pathways. a number of related receptor, along with From this we will attempt to understand which patients benefit most from the drug and also in what specific ways the cancer cells are affected by the treatment.Read moreRead less
Molecular Profiling Of Breast Tumour Stem/Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$308,824.00
Summary
Breast cancer is the commonest cancer in women in many countries including Australia, the USA and the UK. The incidence of breast cancer has been increasing over the last decade however mortality from breast cancer has declined. Although there is debate as to the exact reasons for this decline in mortality, it is clear that the introduction of the screening program as well as improvements in treatment have played a significant role. Nevertheless, a proportion of patients will have disseminated d ....Breast cancer is the commonest cancer in women in many countries including Australia, the USA and the UK. The incidence of breast cancer has been increasing over the last decade however mortality from breast cancer has declined. Although there is debate as to the exact reasons for this decline in mortality, it is clear that the introduction of the screening program as well as improvements in treatment have played a significant role. Nevertheless, a proportion of patients will have disseminated disease at presentation and may not fully respond to treatment. In addition a number of patients will go on to form apparent recurrence of the primary tumour and- or distant metastases following what appears to be complete clearance of a tumour. In recent years a new concept has been put forward that might account for some of these recurrences. It is thought that the cells in a tumour do not all divide at the same rate. Instead some cells only divide rarely, and then give rise to other cells which divide rapidly and form the bulk of the tumour. Since these 'tumour stem cells' are slow cycling they will be resistant to existing chemotherapy because this affects rapidly dividing cells. These resistant cells may then go on to form another tumour. We intend to study these 'tumour stem cells' using a range of techniques that will show us how they differ from both the rest of the tumour cells and the different types of normal cells in the breast. By identifying molecules that are different in the tumour stem cells we will then have new targets for therapies that are designed to target these chemotherapy-resistant cells. Such therapies could be used in the future in conjunction with existing therapies to achieve a greater eradication of breast tumours.Read moreRead less
MODULATING MIC-1 CYTOKINE BIOAVAILABILITY: IMPACT ON TUMOUR BIOLOGY
Funder
National Health and Medical Research Council
Funding Amount
$341,210.00
Summary
MIC-1 cytokine is secreted by many tumour cells. It is commonly secreted as an inactive precursor form of MIC-1 which binds to the extracellular matrix surrounding cells, via its propeptide. This creates latent stores of cytokine which can be released and activated under specific conditions. The propeptide controls the balance between latent stores of inactive MIC-1 precursor and soluble forms of mature bioactive cytokine, which can act on surrounding cells or move into the circulation. The sign ....MIC-1 cytokine is secreted by many tumour cells. It is commonly secreted as an inactive precursor form of MIC-1 which binds to the extracellular matrix surrounding cells, via its propeptide. This creates latent stores of cytokine which can be released and activated under specific conditions. The propeptide controls the balance between latent stores of inactive MIC-1 precursor and soluble forms of mature bioactive cytokine, which can act on surrounding cells or move into the circulation. The significance of these latent stores is underscored by the finding that the level of these stores correlates with prostate cancer outcome, and also that very high circulating levels of active MIC-1 cytokine in the blood, leads to the massive weight loss characteristic of a syndrome called cancer cachexia. This is common in late stages of cancer and is a major contributing factor to the death of cancer patients. Understanding the mechanisms by which latent MIC-1 stromal stores are created and regulated, as well as their role in tumourigenesis, will have major impact on our understanding of the role of this cytokine in cancer. This is essential in order to adequately harness that knowledge for the benefit of patients.Read moreRead less
Tumour Suppressor Networks: The Role Of SHIP-1 And Lyn In Suppressing Haematopoietic Tumours
Funder
National Health and Medical Research Council
Funding Amount
$469,526.00
Summary
Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in ....Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in some instances Lyn and SHIP-1 participate in the same biochemical pathway. We have created mice that are unable to make Lyn protein, and have found that these mice develop blood cell tumours. Mice lacking SHIP-1 develop a number of haematological defects, but die at a young age due to an inflammatory lung condition, making an assessment of the role of SHIP-1 in age-dependent tumour development difficult. We now wish to study the role of SHIP-1 in tumour development, by generating mice that lack SHIP-1 in specific white blood cell compartments. We are also investigating how SHIP-1 and Lyn cooperate in tumour suppression, and we have recently generated mice that simultaneously lack both SHIP-1 and Lyn. Preliminary studies indicate that compound mutant mice develop multiple haematological malignancies. We will fully characterize tumour development in these animals, and determine the molecular basis for this pathology. We will focus on two pathways that have been previously implicated in oncogenesis. These studies will improve our insight into how Lyn and SHIP-1 cooperate in blood cell development, cellular homeostasis and oncogenesis, and add to our biological and biochemical understanding of tumour suppressor networks.Read moreRead less
Analysis Of The Interaction Of The T-cell Oncoproteins Scl And Lmo2 In T Cell Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$179,149.00
Summary
Leukaemic cells frequently contain alterations to the chromosomes which contribute to the generation of the leukaemia by causing the expression of cancer-promoting genes. In the case of T cell acute lymphoblastic leukaemia (T-ALL), the most frequent target of chromosomal alterations is the Stem Cell Leukaemia gene, or SCL. In leukaemic cells, the SCL protein is found to be associated with another protein, called Lmo2, the gene for which is also activated due to chromosomal alterations in T-ALL. ....Leukaemic cells frequently contain alterations to the chromosomes which contribute to the generation of the leukaemia by causing the expression of cancer-promoting genes. In the case of T cell acute lymphoblastic leukaemia (T-ALL), the most frequent target of chromosomal alterations is the Stem Cell Leukaemia gene, or SCL. In leukaemic cells, the SCL protein is found to be associated with another protein, called Lmo2, the gene for which is also activated due to chromosomal alterations in T-ALL. It is thought that these two proteins must bind each other to cause leukaemia, but this has never been proven. This project aims to test whether removal of SCL and Lmo2 is able to stop the progress of leukaemias which they initiate. We will do this by overexpressing SCL and Lmo2 to establish leukaemia in mice, then removing these genes to see if the leukaemia is cured. We will then test whether removal of the endogenous SCL protein is able to stop the onset and progress of leukaemias initiated by Lmo2. We will do this by removing SCL in mice which overexpress Lmo2. Lastly we will generate mutant SCL proteins which are unable to interact with Lmo2, and co-express these along with Lmo2 in mice to assess whether they are able to co-operate with Lmo2 in causing leukaemia. We predict these mutants which are unable to bind to Lmo2 will be unable to co-operate with it in causing leukaemia. This will identify regions of these proteins which can be used as targets for anti-leukaemia drug development.Read moreRead less