The spread of cancer to other organs is responsible for 90% of cancer deaths. This proposal seeks to determine how urological tumours (prostate and bladder) spread around the body. Cancer cell and animal models are an integral component of the research, and together with data obtained in human cancer specimens provide a comprehensive, powerful approach to identify key pathways involved in tumour spread. This is critical for the design of new therapies to treat and-or prevent tumour spread.
INVESTIGATIONS INTO THE BIOLOGICAL FUNCTIONING AND PROGNOSTIC VALUE OF NOVEL METASTATIC MARKERS FOR BREAST CANCER
Funder
National Health and Medical Research Council
Funding Amount
$423,564.00
Summary
Breast cancer is the most malignant tumour of women and, despite great advances in detection and treatment, some 30% of women who present with primary breast cancer eventually relapse or die of their disease. Genetic studies have resulted in the rapid identification of the one-third of women at high risk of developing breast cancer because of a family history of the disease: it is hoped that these women will eventually benefit from advances in gene therapy now being developed. For the majority o ....Breast cancer is the most malignant tumour of women and, despite great advances in detection and treatment, some 30% of women who present with primary breast cancer eventually relapse or die of their disease. Genetic studies have resulted in the rapid identification of the one-third of women at high risk of developing breast cancer because of a family history of the disease: it is hoped that these women will eventually benefit from advances in gene therapy now being developed. For the majority of women developing breast cancer, however, the outcome, or prognosis, remains uncertain. The most important indicators of outcome are obtained by study of the excised cancer tissue, and these relate to the speed of growth of the cancer cells and their ability to migrate, or metastasise, to other sites in the body. Studies of cancer tissue using molecular cell biological methods has enabled the identification of several markers that are proving useful as indicators of outcome, and further understanding of the biological functioning of these markers will enable these molecules to be targetted in new treatments aimed at preventing the spread of the cancer. The present study will examine the appearance of new markers for cell migration among breast cancers and measure their value as indicators of outcome. One molecule in particular may be useful as a therapeutic target since it is used by migrating cells during development but is not expressed by normal (non-cancer) adult tissue cells. Towards this, the project will seek to understand how this molecule functions in cell migration.Read moreRead less
Targeting Prostate Cancer And Metastases With Novel Anti-tumour Drugs.
Funder
National Health and Medical Research Council
Funding Amount
$292,639.00
Summary
Prostate cancer is highly aggressive, causing one death every 4 minutes. It is the most common tumour and is the second highest cause of cancer death in men in Western society. Once it escapes the prostate and spreads to other parts of the body it cannot be cured. Current treatment options are limited and cause debilitating side effects. In this study I will investigate a new class of anticancer drugs developed in my host laboratory for prostate cancer treatment.
Definition Of The Role Of Senescence In Tumour-associated Endothelial Cells.
Funder
National Health and Medical Research Council
Funding Amount
$583,081.00
Summary
'Cellular senescence' is a mechanism to stop cells growing, and it may protect against tumour growth. However, it may also induce changes in cells leading to 'pro-tumour' effects. We have identified a gene - which we have called SEN1 - which induces senescence in the blood vessels of tumours. This gene may cause alterations in the blood supply to the tumour allowing it to grow and to resist chemotherapy. Understanding this gene may allow us to treat cancer by shutting off its blood supply.
Breast cancer is a common disease that is generally incurable if detected after it has spread to other organs. There is a lack of understanding of molecular events that drive the process. Cancers contain several types of host cells that contribute to the growth of the tumour, which can be regarded as wounds that never heal. Host cells are co-opted to promote continued growth of the cancer cells. It is the aim of this project to understand how these host cells promote the spread of breast cancer
The majority of deaths from cancer are due to metastasis, which is the formation of secondary tumours at sites remote from the primary tumour. Metastasis involves conversion of some tumour cells to an invasive, migratory form in a process that is controlled by small genetic regulators known as microRNAs. In this project we will conduct experiments aimed to provide a proof of principle demonstration in mice that microRNAs can be used to block the formation of metastases.
Development And Evaluation Of Biological Reagents Targeting And Inhibiting Function Of The EphA3 Receptor On Tumor Cells
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Eph receptors and their ligands regulate morphogenesis in the embryo; they direct migration and positioning of cells during the formation of tissue layers and organ systems. There is little evidence for a function of Ephs in adult tissues. However, their abundant, un-scheduled occurrence in various malignant tumours, indicates a role in cancer. Human EphA3, the principle subject of this proposal, is not found in adult tissue but is present at high levels in lung, kidney and brain tumours, leukem ....Eph receptors and their ligands regulate morphogenesis in the embryo; they direct migration and positioning of cells during the formation of tissue layers and organ systems. There is little evidence for a function of Ephs in adult tissues. However, their abundant, un-scheduled occurrence in various malignant tumours, indicates a role in cancer. Human EphA3, the principle subject of this proposal, is not found in adult tissue but is present at high levels in lung, kidney and brain tumours, leukemia and malignant melanoma. High levels of EphA3 and corresponding ligands correlate with melanoma progression, and EphA3 stimulation triggers repulsion and detachment of melanoma cells. It is likely that Eph A3 is involved in release and spreading of tumour cells during melanoma progression. We have characterised reagents, the soluble EphA3 ligand and a monoclonal anti-EphA3 antibody, which bind EphA3 with high affinity and specificity. We will use these two proteins, or modified forms containing attached radiochemicals or cytotoxins, to target human tumours that were implanted into into immuno-deficient mice as animal model system. Our studies will determine if the specificity of our reagents, suggested from previous in-vitro studies, will allow imaging of EphA3 containing tumours, and effect their targeted killing. We will also use a tissue culture model, containing artificial epidermal and dermal layers of skin cells, to study if an inhibitory form of the EphA3 ligand will affect the invasiveness of EphA3 positive, metastatic melanoma cells. Furthermore, we will identify essential parts of this ligand to develop inhibitors with improved pharmacological properties. Together, our studies will establish the role for EphA3 in cancer progression and to assess the efficacy of EphA3 targeting for tumor killing and prevention of metastasis. We envision that this will provide the groundwork for Eph-specific reagents with anti-metastatic action in cancer therapy.Read moreRead less
How Does Fra-1 Regulate The Invasive Properties Of Tumour Cells?
Funder
National Health and Medical Research Council
Funding Amount
$468,119.00
Summary
Most cancer deaths occur when tumours spread and destroy vital body functions. The invasion of tumour cells into surrounding tissue is a critical step during the spread of cancer. This project aims to unravel the molecular mechanisms that control the ability of tumour cells to invade into surrounding tissue and subsequently spread to other sites in the body. We expect to identify potential targets to better diagnose and treat the spread of cancer.
MMP13 is upregulated in cancer cells and in the tissue that forms around the cancer (stroma). A new MMP13-specific inhibitor reduces breast cancer growth in a mouse model, both at the primary site and also in bone. We will determine the role of MMP13 made by the cancer cells and stroma, respectively, extend the inhibitor work, and identify proteins being cleaved by MMP13. Being a late-stage manifestation, bone metastasis may represent an important clinical trial setting for MMP inhibitors.