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
The Breast Cancer Biospecimen Resource will consist of stored samples of the majority of newly diagnosed breast cancers in NSW and through the Australian and New Zealand Breast Cancer Trials Group together with accurate, prospectively tracked clinical data on each specimen. This facility will serve as a model for extension of similar procedures to other common Australian cancers including cancers of the lung, bowel, prostate and melanoma. Research that is facilitated by this Resource holds real ....The Breast Cancer Biospecimen Resource will consist of stored samples of the majority of newly diagnosed breast cancers in NSW and through the Australian and New Zealand Breast Cancer Trials Group together with accurate, prospectively tracked clinical data on each specimen. This facility will serve as a model for extension of similar procedures to other common Australian cancers including cancers of the lung, bowel, prostate and melanoma. Research that is facilitated by this Resource holds real promise for improving patient selection for treatment. This will return a significant humanitarian and cost saving benefit. In addition this advance would also maximise the benefit of population mammographic screening.Read moreRead less
Proteomic Screening For Apoptotic Markers In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
The induction of apoptosis, or programmed cell death, is a key factor in the response of tumours to chemotherapeutic agents and ionising radiation; therefore biological markers that predict the clinical outcome to these therapies are needed. Over the past 2 years, our laboratory has developed techniques of protein analysis to evaluate changes in proteins during apoptosis caused by chemotherapeutic agents. Preliminary protein profiling studies of apoptosis induction in human breast cancer cell li ....The induction of apoptosis, or programmed cell death, is a key factor in the response of tumours to chemotherapeutic agents and ionising radiation; therefore biological markers that predict the clinical outcome to these therapies are needed. Over the past 2 years, our laboratory has developed techniques of protein analysis to evaluate changes in proteins during apoptosis caused by chemotherapeutic agents. Preliminary protein profiling studies of apoptosis induction in human breast cancer cell lines showed time-dependent decreases in two proteins, identified as S100A6 and ubiquitin. Both are known to be important in cell function. In the proposed project we will build on our preliminary findings to provide important new information central to the understanding of cancer cell biology and apoptosis in addition to evaluating the ability of anti-cancer treatments to induce apoptosis. Using a combination of protein analysis technologies, this project has the potential to provide reliable and novel biomarkers which will indicate the efficacy and selectivity of anti-cancer treatments in inducing tumour cell death. The knowledge gained in this project will aid clinical assessment of the response to cancer treatment(s) in patients in the form of specific screening assays, and may result in identification and development of effective new agents for cancer treatment and prevention. Furthermore, the outcomes of this project will increase our understanding of fundamental cancer cell biology and apoptosis.Read moreRead less
mTOR signalling in serous ovarian cancer. Serous ovarian cancer is the most aggressive and lethal gynaecological cancer in Australian women. Activation of Mammalian Target of Rapamycin (mTOR) is frequently observed and associated with poor prognosis in ovarian cancer patients. However, the mechanisms dysregulating mTOR in the pathogenesis of ovarian cancer are unknown. In preliminary studies, deletion of genes regulating mTOR signalling in up to 60 per cent of human serous ovarian cancer patien ....mTOR signalling in serous ovarian cancer. Serous ovarian cancer is the most aggressive and lethal gynaecological cancer in Australian women. Activation of Mammalian Target of Rapamycin (mTOR) is frequently observed and associated with poor prognosis in ovarian cancer patients. However, the mechanisms dysregulating mTOR in the pathogenesis of ovarian cancer are unknown. In preliminary studies, deletion of genes regulating mTOR signalling in up to 60 per cent of human serous ovarian cancer patients was observed. This project will provide mechanistic details of involvement of mTOR signalling in pathogenesis of the serous ovarian carcinoma, and develop a rationale for targeting mTOR pathway in these patients. Read moreRead less
Total Laparoscopic Hysterectomy (TLH) Vs. Total Abdominal Hysterectomy (TAH) For The Treatment Of Endometrial Cancer
Funder
National Health and Medical Research Council
Funding Amount
$809,860.00
Summary
The LACE study is a clinical trial comparing two types of surgery for women with early-stage cancer of the inner lining of the uterus, known as endometrial cancer. Treatment for endometrial cancer involves removal of the uterus, tubes, ovaries and lymph nodes. Traditionally this has been performed by open surgery via an abdominal incision. Open surgery is effective for endometrial cancer, but it is highly invasive, resulting in visible scarring, tissue damage, blood loss and a fairly high risk o ....The LACE study is a clinical trial comparing two types of surgery for women with early-stage cancer of the inner lining of the uterus, known as endometrial cancer. Treatment for endometrial cancer involves removal of the uterus, tubes, ovaries and lymph nodes. Traditionally this has been performed by open surgery via an abdominal incision. Open surgery is effective for endometrial cancer, but it is highly invasive, resulting in visible scarring, tissue damage, blood loss and a fairly high risk of complications. Laparoscopic surgery, commonly referred to as keyhole surgery, is a new approach to removing the uterus, tubes, ovaries and lymph nodes. Preliminary results from this less invasive surgery have been extremely encouraging. Laparoscopic surgery is practical and safe in treating endometrial cancer, while also resulting in less tissue damage, lower blood loss, less pain and a shorter recovery period in hospital. The LACE study aims to give definitive answers about the results offered by laparoscopic surgery in treating women with early stage endometrial cancer. The primary aim is to investigate whether the treatment of endometrial cancer using laparoscopic surgery is as good as that using open surgery. Secondary aims look at whether laparoscopic surgery provides more benefits compared to open surgery for endometrial cancer, such as: - improvements in the quality of life post-surgery, - reduced number of early and late surgery-related complications, - shorter stays in hospital, - fewer blood transfusions required, - less pain post-surgery, and hence fewer pain-killers. The LACE study is already under way, with recruitment on target for Stage 1. This application seeks funding for Stage 2, to expand recruitment from 2007. The outcomes of the trial will have a significant bearing on the future choice of treatment for endometrial cancer. Therefore the study will impact many patients around the world, including ~2000 women every year in Australia.Read moreRead less
Pathophysiology Of Oxaliplatin-induced Nerve Dysfunction And Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$281,255.00
Summary
When treating patients diagnosed with cancer, nerve dysfunction is a common complication of chemotherapy, particularly with oxaliplatin. Neurological symptoms develop in up to 90% of patients following oxaliplatin treatment. Neurotoxicity is a key factor in determining the dosage and frequency of current chemotherapeutic agants. Oxaliplatin therapy results in disabling neurological effects. Onset of neuropathy can be relatively fast or in other cases may develop months after therapy has been com ....When treating patients diagnosed with cancer, nerve dysfunction is a common complication of chemotherapy, particularly with oxaliplatin. Neurological symptoms develop in up to 90% of patients following oxaliplatin treatment. Neurotoxicity is a key factor in determining the dosage and frequency of current chemotherapeutic agants. Oxaliplatin therapy results in disabling neurological effects. Onset of neuropathy can be relatively fast or in other cases may develop months after therapy has been completed. The other chief problems encountered during chemotherapy can be overcome: nausea and vomiting can be treated; myelosuppression can be reversed. End organ toxicity such as neuropathy cannot be controlled. Despite the high incidence of neuropathy due to chemotherapy, the mechanisms involved remain poorly understood, particularly with newer therapies. The aim of the present study is to measure nerve function in oncology patients treated with oxaliplatin using a novel protocol, attempting ultimately to identify aspects of dysfunction that correlate with clinical abnormalities, so helping to pin-point the mechanisms responsible for neuropathy. Once identified, management strategies can be developed to better target the prevention and treatment of neuropathy in oncology patients treated with chemotherapy.Read moreRead less
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
The Trans Tasman Radiation Oncology Group is an experienced research group conducting cancer clinical trials involving radiotherapy (RT) in order to improve cure rates, quality of life and to reduce side-effects of treatment. Fifty per cent of all cancer patients need RT as part of their treatment. The aim of the proposal is to strengthen the quality and safety of RT trials by (a) enabling rapid review and checking of treatment by electronic means and (b) improve trial design.
Availability of ethically consented, clinically annotated human cancer tissue is a key determinant of the international competitiveness of Australian biomedical researchers. This project will provide a structured national network to collect, process and disseminate tumour tissue; strategically target specific tumour types such as mesothelioma and rare paediatric tumours that can only be collected in substantial numbers through the formation of such a network and provide infrastructure that can b ....Availability of ethically consented, clinically annotated human cancer tissue is a key determinant of the international competitiveness of Australian biomedical researchers. This project will provide a structured national network to collect, process and disseminate tumour tissue; strategically target specific tumour types such as mesothelioma and rare paediatric tumours that can only be collected in substantial numbers through the formation of such a network and provide infrastructure that can be contracted by clinical and translational researchers. The project builds on a wealth of experience in tissue banking, large-scale molecular genetic and genomic studies in breast, ovarian, colorectal cancers and mesothelioma, and on an established consortium _ the Australasian Biospecimen Network.Read moreRead less