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
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
Signalling Networks As Targets For Antibody Therapy In Glioma.
Funder
National Health and Medical Research Council
Funding Amount
$526,683.00
Summary
Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. It is also possible to generate antibodies that bind to receptors on the surface of can ....Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. It is also possible to generate antibodies that bind to receptors on the surface of cancer cells and block their function. If you target a receptor critical to the growth or survival of a cancer cell in this way, then swtiching-off this signal may inhibit tumor growth. In this proposal we plan to test a panel antibodies that recognize receptors important to the growth of brain cancer. Two of these antibodies have been generated and the other two will be made as part of this proposal. A key aspect of this proposal will be testing these antibodies in combination to determine how many receptors need to be targeted in order to get complete tumor regressions in animal models. Overall this work will help us identify new therapeutic strategies for the treatment of brain cancer. Finally, we will also analyze the way different receptors interact together in brain cancer cells.Read moreRead less
Identification Of Oncogenes From Myeloid Leukaemias By Retroviral Expression Cloning
Funder
National Health and Medical Research Council
Funding Amount
$552,000.00
Summary
The success rates for treatment of most myeloid leukaemias remain relatively poor, with 5-year survival rates of 40-50% overall. Thus there is a clear need for improvements in diagnosis and particularly treatment. An important and relatively new approach for doing this is to target the specific molecular and genetic alterations that lead to these diseases. This requires the identification of these alterations, particularly the oncogenes ('cancer genes') that cause or contribute to the various fo ....The success rates for treatment of most myeloid leukaemias remain relatively poor, with 5-year survival rates of 40-50% overall. Thus there is a clear need for improvements in diagnosis and particularly treatment. An important and relatively new approach for doing this is to target the specific molecular and genetic alterations that lead to these diseases. This requires the identification of these alterations, particularly the oncogenes ('cancer genes') that cause or contribute to the various forms of myeloid leukaemia. However in many cases (up to 50%), the key oncogenes involved in have not and-or cannot be identified using current methods. This project aims to develop and apply a powerful technique called 'retroviral expression cloning' for the identification of oncogenes involved in myeloid leukaemia. In essence our approach is to identify oncogenes from myeloid leukaemia samples on the basis of their function - that is, by virtue of their ability to induce dysregulated or uncontrolled growth of blood-derived cells in culture.Read moreRead less
THE REGULATORY MECHANISM OF HAEM OXYGENASE PROTECTION AGAINST PHOTOIMMUNOSUPPRESSION AND SKIN CANCER
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
Current dogma holds that UVA radiation adds to UVB damage in the skin. However we have identified a window of UVA doses, easily achievable from daytime sunlight exposure, that do not cause sunburn and are not immunosuppressive, but that significantly attenuate the damaging effects of UVB. In mice the mechanism partially depends on the UVA-upregulated cytokine interferon-gamma, and strongly on the UVA-inducible antioxidant enzyme haem oxygenase-1 (HO-1). This project aims to establish how the HO- ....Current dogma holds that UVA radiation adds to UVB damage in the skin. However we have identified a window of UVA doses, easily achievable from daytime sunlight exposure, that do not cause sunburn and are not immunosuppressive, but that significantly attenuate the damaging effects of UVB. In mice the mechanism partially depends on the UVA-upregulated cytokine interferon-gamma, and strongly on the UVA-inducible antioxidant enzyme haem oxygenase-1 (HO-1). This project aims to establish how the HO-1 gene is regulated by UVA. Available data from cultured human skin cells suggest that HO-1 is UVA-inducible in fibroblasts but not keratinocytes, whereas we found both cell types respond in mouse skin, keratinocytes most actively. We will ascertain whether a species difference, or an anomaly in cultured cells, underlies these discrepancies. With human skin grafted onto immunodeficient SCID mice, we will study impaired immune function, an important prerequisite for cancer, compared with mouse skin in vivo. Using molecular biology techniques with this model, we will monitor the activity of the transcription factor Bach 1, known to bind to the DNA of the HO-1 promoter region to repress the gene normally, but reversibly by haem-binding, and the corresponding activity of HO-1, during immunoprotective (UVA exposure, haem elevated) conditions. Immunoprotection may result from binding by Bach 1 of haem released from microsomal proteins by UVA, its release from DNA and thus derepression of HO-1. We will seek evidence of a role for skin cytokines in modifying Bach 1 binding, and for Bach 1 and HO-1 actions during photocarcinogenesis induction with chronic UV exposure. The significance of the outcome of the studies will be in understanding how a natural ameliorating pathway induced by UVA radiation could be utilised for superior photoprotection strategies for skin cancer susceptible humans.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
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