Mechanisms Of Action Of The Zinc Finger Protein LMO4 In Breast Oncogenesis
Funder
National Health and Medical Research Council
Funding Amount
$272,859.00
Summary
Breast cancer is the most common cancer to strike Australian women, affecting one in 12 women by age 75. Although treatment of breast cancer has substanially improved over the last few years, approximately 25% of women diagnosed with this cancer will die from the disease. A major objective of cancer research is the identification of genes involved in tumour development and definition of their precise role in both normal and cancer cells. The design of new effective therapeutic inhibitors of canc ....Breast cancer is the most common cancer to strike Australian women, affecting one in 12 women by age 75. Although treatment of breast cancer has substanially improved over the last few years, approximately 25% of women diagnosed with this cancer will die from the disease. A major objective of cancer research is the identification of genes involved in tumour development and definition of their precise role in both normal and cancer cells. The design of new effective therapeutic inhibitors of cancer requires an understanding of the basic molecular and cellular biology behind the genetic changes that contribute to cancer. The focus of our research is to understand normal cellular mechanisms that drive growth and differentiation of breast tissue, and those changes that lead to breast cancer. We are particularly interested in 'master regulators' that are located in the cell nucleus. Nuclear regulators have been implicated in many different types of cancer and leukaemias. We aim to identify the key regulators in breast tissue, characterising both their biological roles and mechanism of action, with the ultimate view of understanding how they divert a normal cell to a cancerous cell. This proposal centres on the characterisation of a specific nuclear regulatory molecule, LMO4, which we have demonstrated to be overexpressed in 56% of human primary breast cancers. Significantly, we have recently shown that overexpression of LMO4 predicts poor outcome in breast cancer patients. We have also shown that this protein interacts with the breast tumour suppressor protein BRCA1, as well as a number of other proteins. These studies will include defining LMO4 s role in governing cell growth in breast cancer cells and that of the proteins that bind to this regulator. We will also assess the role of LMO4 in controlling cell invasion and metastasis of breast cancer cells in mouse models since we have preliminary evidence that it may be a critical regulator of these processes.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
Inhibition Of Breast Cancer Metastasis Through Targeting Of Laminin-10 Function
Funder
National Health and Medical Research Council
Funding Amount
$391,241.00
Summary
Breast cancer affects 1 in 11 women in Australia. Whilst breast cancer is highly curable when detected early, current treatments are ineffective when the disease has spread to other organs such as bone and lungs. Thus, novel therapies for the treatment of advance disease are urgently needed. We have found that laminin-10, a protein present in the breast and thought to control normal breast development and maturation, is particularly abundant in aggressive tumours as well as in those that have sp ....Breast cancer affects 1 in 11 women in Australia. Whilst breast cancer is highly curable when detected early, current treatments are ineffective when the disease has spread to other organs such as bone and lungs. Thus, novel therapies for the treatment of advance disease are urgently needed. We have found that laminin-10, a protein present in the breast and thought to control normal breast development and maturation, is particularly abundant in aggressive tumours as well as in those that have spread to bone and lungs suggesting that this protein may play a role in the dissemination of breast cancer cells to other organs. Consistent with this, we have found that laminin-10 stimulates breast tumour cell adhesion and movement in culture, two activities required for successful metastasis of tumour cells. The overall objective of the projects is to demonstrate that breast cancer metastasis can be inhibited by interefering with the function of laminin-10. To this end, we will measure the effect of blocking the production of LN-10 in breast tumour cells on their ability to metastasise. Alternatively, we will test fragments of laminin-10 for their ability to block laminin-10-induced tumour cell growth and movement (required for their escape from the breast) and viability (required for their establishment in distant organs). We will generate antibodies against the most inhibitory fragments and test their effect on spontaneous metastasis in a clinically relevant mouse model of breast cancer metastasis in an attempt to stop-reverse the progression of the disease. If successful, this project will provide the foundation for the development novel inhibitors targeting laminin-10 for the treatment of patients with advanced breast cancer.Read moreRead less
Role Of The Tetraspanin CD151 In Epithelial Biology And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
A cell surface protein identified in this laboratory has been linked to cancer progression and metastasis. This project aims to examine the molecular basis of the action of the protein in regulating cell migration, and to establish model systems to provide definitive evidence as to its role in the development and progression of cancer. The models will also provide systems for future studies to evaluate the potential of antibodies and other inhibitors of the action of this protein as therapeutics ....A cell surface protein identified in this laboratory has been linked to cancer progression and metastasis. This project aims to examine the molecular basis of the action of the protein in regulating cell migration, and to establish model systems to provide definitive evidence as to its role in the development and progression of cancer. The models will also provide systems for future studies to evaluate the potential of antibodies and other inhibitors of the action of this protein as therapeutics in a range of human cancers.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
In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, ....In this project we aim to define the role of the Siah proteins in tumour angiogenesis and inflammatory responses. Hypoxia, a decrease in oxygen tension, places constrains on tumour growth where access to oxygen is yet to be established via new blood vessel formation. In addition hypoxia is common in areas of inflammation and wound healing, where blood vessels have been shut down to help in recovery. With the use of our Siah knockout mice we have a unique model that allows us, for the first time, to investigate the role of Siah in the hypoxia signalling cascade. How cells sense and react to low oxygen levels is complex and involves several proteins. A key protein is called Hypoxia induced factor, Hif-1. It accumulates under hypoxia and is responsible for the expression of genes enabling the cell to tolerate and function under hypoxic conditions. tolerate and function under hypoxic conditions, which is involved in new blood vessel formation. PHD protein directs the degradation of Hif1, while Siah directs the degradation of PHD, when oxygen is limiting. Loss of Siah proteins (eg in our knockout models) leads to an increase in PHD proteins under hypoxia thus no stabilisation of Hif-1 and impaired response to hypoxia. Thus, sitting on the top of a cascade, which controls the trashing of proteins in the cell (focus of this year's Nobel price for medicine), Siah has primary control on the response to oxygen deprivation. The relative immunity of multicellular organisms to acquired defects is through redundancy. Oxygen is a unique case, for which organisms can not bypass the defect via redundancy, making it an attractive target for future therapy. Therefore, understanding the molecular and cellular response to hypoxia may allow us to identify key molecules which could be targeted for the development of novel anti inflammatory and cancer drugs. The scope of this study is to understand the key role of Siah utilising our knockout mice in models of inflammation and cancer.Read moreRead less
Value Of Androgen Deprivation And Bisphosphonate In Patients Treated By Radiotherapy For Localised Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$2,533,827.00
Summary
Following on from significant findings in the TROG 96.01 trial, the 03.04 trial, known as the RADAR trial was developed. This is a large-scale randomised controlled clinical trial currently conducted at 23 cancer treatment centres throughout Australia and New Zealand. The RADAR trial aims to recruit 1000 men with localised but inoperable prostate cancer. It was anticipated that the length of time required to enrol 1000 participants to the trial would be 5 years. However, because enrolment has ex ....Following on from significant findings in the TROG 96.01 trial, the 03.04 trial, known as the RADAR trial was developed. This is a large-scale randomised controlled clinical trial currently conducted at 23 cancer treatment centres throughout Australia and New Zealand. The RADAR trial aims to recruit 1000 men with localised but inoperable prostate cancer. It was anticipated that the length of time required to enrol 1000 participants to the trial would be 5 years. However, because enrolment has exceeded expectations and 728 patients have already been recruited, it is anticipated that the recruitment target will be reached in mid 2007. Patients are randomly assigned to receive one of four treatment options in the RADAR trial. The first option: Option A: Radiation Therapy and 6 months of Hormone Therapy (Leuprorelin acetate), is currently the standard of care. Option C is a further 12 months of hormone therapy after the current standard of care. Two of the options (B and D) are identical to options A and C except that subjects also receive 18 months of zoledronate (a 'bone' drug) in addition to hormone therapy and radiotherapy. The main goal of the RADAR trial is to determine whether 12 months of hormone therapy using Leuprorelin acetate starting immediately after standard therapy (ie 6 months of Leuprorelin acetate before and during radiotherapy) will reduce risk of return of the cancer, either within the prostate region or at remote sites in the body, and prolong life. An additional goal is to see whether 18 months of bisphosphonate therapy (bone density therapy) using zoledronate will reduce the risk of cancer returning in the bones as well as stopping dangerous bone thinning which can sometimes be caused by hormone therapy. The trial also seeks to determine whether the additional therapy given in this trial alters quality of life.Read moreRead less