The Roles Of EZH2 And FOXO1A In CNS-PNET Pathogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$467,517.00
Summary
Although CNS-PNETs are the most common embryonal CNS tumours of childhood and cause significant mortality and morbidity, there is a very limited understanding of the pathogenesis of this aggressive disease. This situation is a major handicap to the development of more specific and effective therapies. While a better understanding of the fundamental pathology of CNS-PNETs will have immediate diagnostic implications, the elucidation of the biochemical pathways that are disrupted in these tumours w ....Although CNS-PNETs are the most common embryonal CNS tumours of childhood and cause significant mortality and morbidity, there is a very limited understanding of the pathogenesis of this aggressive disease. This situation is a major handicap to the development of more specific and effective therapies. While a better understanding of the fundamental pathology of CNS-PNETs will have immediate diagnostic implications, the elucidation of the biochemical pathways that are disrupted in these tumours will facilitate the design of new drugs that are specifically directed towards the critical proteins in these pathways. The identification of specific genes and-or pathways that are deregulated in CNS-PNET cells is essential for the development of safer, more directed, and more effective therapies that are urgently required for the treatment of those with this devastating disease.Read moreRead less
Role Of Betaglycan In Gonadal And Adrenal Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$487,500.00
Summary
TGF-beta and inhibin are related multifunctional growth factors which regulate a number of important cellular functions, including proliferation, differentiation, and survival. Betaglycan is a cell-surface protein that binds both inhibin and TGF-beta. Betaglycan appears to regulate the binding and availability of the TGF-betas and inhibins to their signaling receptors, and its presence on the cell surface increases the efficiency of TGF-beta and inhibin function. Deletion of the inhibin gene in ....TGF-beta and inhibin are related multifunctional growth factors which regulate a number of important cellular functions, including proliferation, differentiation, and survival. Betaglycan is a cell-surface protein that binds both inhibin and TGF-beta. Betaglycan appears to regulate the binding and availability of the TGF-betas and inhibins to their signaling receptors, and its presence on the cell surface increases the efficiency of TGF-beta and inhibin function. Deletion of the inhibin gene in mice produces tumours in the ovary, testis, and adrenal gland in 100% of the mice. In this current proposal, we will delete the betaglycan gene in the primary target tissues for inhibin (the anterior pituitary and gonads). The hypothesis we are testing is that the loss of a co-receptor for inhibin (i.e. betaglycan) results in a loss of cellular sensitivity to inhibin, thus resulting in altered growth characteristics which predispose the gonads and adrenals to cancer. We will examine these cells in culture and in living animals to determine whether our hypotheses are correct. We will also conduct a series of histological, biochemical, and biological experiments in order determine the underlying causes of any observed growth dysregulation. This work is expected to yield information relevant to the role of betaglycan in inhibin-TGFb-regulated processes in normal and cancerous growth, which may allow future design of therapies for cancer.Read moreRead less
Aromatase Regulation By P53 And HIF-1alpha In Obesity And Post-menopausal Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$607,523.00
Summary
Current hormone therapy for breast cancer using inhibitors of oestrogen production results in serious side-effects including bone loss, joint pain and possibly cognitive issues. Our current work is aimed at understanding how oestrogen production is regulated with the goal of developing breast-specific inhibitors of oestrogen production to obviate these problems. In addition, this work is aimed at devising therapeutic intervention to break the linkage between obesity and breast cancer.
The Identification Of Novel Genes Involved In The Initiation And Development Of Thyroid Neoplasia
Funder
National Health and Medical Research Council
Funding Amount
$227,545.00
Summary
Thyroid cancer is the most frequently diagnosed endocrine malignancy, comprising 1% of all human malignancy. However, its actual occurrence indicated by autopsy studies may be as high as 10%. To date, a number of genes, both oncogenes (genes that are inappropriately switched on and take part in the process of tumour development) and tumour suppressor genes (genes that are switched off and lose their protective role against tumour development), have been implicated in the development of thyroid c ....Thyroid cancer is the most frequently diagnosed endocrine malignancy, comprising 1% of all human malignancy. However, its actual occurrence indicated by autopsy studies may be as high as 10%. To date, a number of genes, both oncogenes (genes that are inappropriately switched on and take part in the process of tumour development) and tumour suppressor genes (genes that are switched off and lose their protective role against tumour development), have been implicated in the development of thyroid cancer. However mutations, mistakes in the genetic code, of these genes account for only a small percentage of thyroid tumours and none of these genes have been shown to be useful as clear prognostic markers for tumour progression or aggressiveness. The merging of the 2 fields of cytogenetics (the study of chromosomes) and molecular genetics (the study of genes at the DNA and RNA level) has strengthened our ability to understand the process of tumour development. We are proposing use of a technique called Comparative Genomic Hybridisation to aid in the identification of new genes associated with tumour development in both benign and malignant thyroid disease. This technique has already been used to aid in the location of genes with a role in ovarian and brain cancer and in some familial syndromes characterised by breast and gastrointestinal malignancies. This method involves the detection of regions of chromosomal amplifications or deletions in tumour DNA that is fluorescently labelled (green), mixed with normal human DNA also fluorescently labelled (red). If the tumour contains regions of amplification (likely housing an oncogene), analyses show increased green fluorescence and if deletions are present (likely housing a tumour suppressor gene), analyses show increased red fluorescence. Chromosomal regions identified by this method will be further analysed to identify the precise genes they contain and establish a role for these genes in the development of thyroid tumours.Read moreRead less
Development Of A Scorpion Toxin For Tumour Imaging
Funder
National Health and Medical Research Council
Funding Amount
$529,577.00
Summary
The aim of this project is to develop a tool for visualising tumours during surgery. Surgical removal of tumours remains the foundation of cancer treatment, but the ability to distinguish the margin between cancerous and healthy cells is imprecise. We will explore the potential of a scorpion toxin that selectively targets cancer cells, as a tumour imaging agent. This project has the potential to dramatically enhance patient survival as a result of improving treatments for cancer.
The Role Of TAP And MHC Class I Expression In The Response To Melanoma Immunotherapy Using Autolgous Dendritic Cells
Funder
National Health and Medical Research Council
Funding Amount
$337,811.00
Summary
Treatment for patients with malignant melanoma whose disease has spread, or metastasised, to sites distant from the original melanoma is usually unsuccessful. At this stage of the disease there is no known curative treatment with conventional surgery, radiation or chemotherapy. Occasionally, however, melanoma in its early stages is successfully dealt with by the natural response of the immune system. In these cases, the immune system generates cancer-controlling killer T lymphocytes that enter t ....Treatment for patients with malignant melanoma whose disease has spread, or metastasised, to sites distant from the original melanoma is usually unsuccessful. At this stage of the disease there is no known curative treatment with conventional surgery, radiation or chemotherapy. Occasionally, however, melanoma in its early stages is successfully dealt with by the natural response of the immune system. In these cases, the immune system generates cancer-controlling killer T lymphocytes that enter the melanoma and kill the tumour cells. Killer T lymphocytes are generated by the lymph glands when the immune system is presented with melanoma cell components, or antigens, by specialised cells known as dendritic cells. This project consists of a clinical trial that aims to boost the natural ability of the immune system to generate killer cells by growing dendritic cells from the blood, mixing them with melanoma antigens, and then inject the mixture. When injected into the skin, dendritic cells quickly move to lymph glands to generate killer T lymphocytes. T lymphocytes can find their way to melanoma deposits all over the body. The reasons for response or non-response to the vaccination will particularly be assessed in this project.Read moreRead less
This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does ....This is a study of the biological system of epigenetics. Every cell in our body has the same genetics, or library of information contained in the form of DNA sequence. Epigenetics is the system that controls how this DNA is used in a particular situation, or what books are opened and read. During embryonic development, cells know what they want to become, e.g., a muscle cell, and, once they take on an identity, remember that they are when they duplicate themselves during growth. Epigenetics does not achieve this through changing genetics the library always stays intact. Rather, it acts by using proteins or chemicals to make DNA functional in one way, or another. Genomic imprinting is a special type of epigenetics. While an embryo has received identical genetic information from each of its parents, the epigenetic information received from each parent was not entirely the same. Some genes which behave differently according to what parent they came from. For example, a gene that makes a growth factor protein is active only if received from the father. If received from the mother, it is inactive, and makes no protein. Genes behaving in this way are known as imprinted genes. We are trying to discover what epigenetic mechanisms are behind this behaviour of imprinted genes. One way we are approaching this problem is to study germ cells the cells giving rise to eggs and sperm. These cells are unusual in that their imprinted genes behave in the same way regardless of whether they were received from the mother or father, i.e., like any other gene. If we can understand why this is the case, we will be better able to understand why imprinted genes behave the way they do in the rest of the cells of the body. Broadly, the mechanisms we uncover should further our understanding of germ cell development, gene expression, and disease. Perturbations in the epigenetic profile are likely causes of human disease, including cancer.Read moreRead less
Towards Predicting Brain Deformations For Image-guided Neurosurgery
Funder
National Health and Medical Research Council
Funding Amount
$304,281.00
Summary
We will significantly improve the efficiency of image-guided neurosurgery for brain tumours by creating a novel system to improve intra-operative visualisation and navigation utilising realistic prediction of brain deformations based on a biomechanical model. The system will create an augmented reality visualisation of the intra-operative configuration of the patient's brain merged with high resolution pre-operative imaging data in order to better localise the tumour and critical healthy tissues ....We will significantly improve the efficiency of image-guided neurosurgery for brain tumours by creating a novel system to improve intra-operative visualisation and navigation utilising realistic prediction of brain deformations based on a biomechanical model. The system will create an augmented reality visualisation of the intra-operative configuration of the patient's brain merged with high resolution pre-operative imaging data in order to better localise the tumour and critical healthy tissues.Read moreRead less