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Defining The Role Of Microphthalmia-associated Transcription Factor (MITF) In Melanoma Heterogeneity By Real-time Cell Cycle Imaging
Funder
National Health and Medical Research Council
Funding Amount
$613,705.00
Summary
Metastatic melanoma is highly therapy-resistant. Modern targeted therapy is promising but suffers from rapid onset of drug resistance. Tumours consist of zones of fast growing cells next to zones of dormant cells. This tumour heterogeneity is one of the reasons for cancer drug resistance, as cells in different growth states respond differently to drugs. By understanding the causes of tumour heterogeneity we will set the basis for innovative clinical approaches against this devastating disease.
Aberrant Transcriptional Signalling In The Progression And Metastasis Of Melanoma.
Funder
National Health and Medical Research Council
Funding Amount
$353,033.00
Summary
There are currently no treatments that have any impact on decreasing mortality from metastatic melanoma. We have found 2 new variants in melanoma that may control the tumour growing and invading around the body. This study will examine the protein containing these changes with the aims of finding how they function differently, to identify their roles in the formation of melanoma, as well as to identify new targets for prevention and treatment of metastatic disease.
New Role For The E3 Ligase E6AP In The Control Of Cell Motility And Invasion
Funder
National Health and Medical Research Council
Funding Amount
$462,162.00
Summary
Cell motility and invasion are fundamental process in normal cellular functions, however, when deregulated they can lead to metastatic cancer, a leading cause of cancer mortality and morbidity worldwide. Detailed understanding of the mechanisms governing these processes is essential for the development of new targets to prevent metastatic cancer. We discovered a protein that control these processes, which renders it an important target to investigate.
A Fluorescent Zebrafish Model Of Endodermal Cell Migration.
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
The most catastrophic event in cancer progression is when individual cancer cells move to other areas of the body and develop into secondary tumours. This very complex process shows striking similarities to cell movements during embryogenesis. In this project, we use a model system, the zebrafish, to analyse how cells move during embryogenesis. We will determine the genes required for cell movements in the zebrafish embryo, so we can find the corresponding genes in human cancers.
Every cell in our body has an intrinsic orientation that is controlled by a universal set of genes known as polarity genes. Loss of this orientation is a common and early feature of cancer. We have identified the gene Scribble as a gene that controls cell orientation and is essential to prevent the development of prostate cancer. We propose experiments to discover how Scribble controls prostate cancer and whether it can be used to better predict outcome for prostate cancer patients.
Regulation Of Gastric Tumour Invasion And Growth By Gp130 Activating Cytokines.
Funder
National Health and Medical Research Council
Funding Amount
$625,642.00
Summary
Gastric cancer is a major cause of morbidity and death worldwide. We have previously established a very informative animal model of this disease which has facilitated a new understanding of the diverse role of the IL-6 family of cytokines in regulating gastric tumour growth and dissemination to distant organs. This proposal will focus on how the main members of this cytokine family, namely IL-6 and IL-11, inhibit gastric tumour invasion to other organs, and promote tumour growth respectively . A ....Gastric cancer is a major cause of morbidity and death worldwide. We have previously established a very informative animal model of this disease which has facilitated a new understanding of the diverse role of the IL-6 family of cytokines in regulating gastric tumour growth and dissemination to distant organs. This proposal will focus on how the main members of this cytokine family, namely IL-6 and IL-11, inhibit gastric tumour invasion to other organs, and promote tumour growth respectively . An understanding of these processes will aid in designing therapeutic interventions specific for each cytokine and which may lead to drugs aimed at limiting or reversing this disease.Read moreRead less
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
Molecular And Epidemiological Investigation Of Cutaneous Squamous Cell Carcinoma Of The Head And Neck With Perineural Invasion
Funder
National Health and Medical Research Council
Funding Amount
$42,862.00
Summary
Queensland has the highest recorded rates of skin cancer in the world. Invasion into nearby nerves or �perineural invasion� occurs in approximately 5% of cases. This signifies that the tumour is aggressive and able to spread along nerves back to the brain and reduce survival. Why some tumours invade nerves remains unclear. This project will study the factors involved and the characteristics of affected patients to enable a better understanding of the disease and potentially improve treatment.
Role Of A Novel Tks5-Nck Signaling Pathway In Cancer Invasion
Funder
National Health and Medical Research Council
Funding Amount
$560,434.00
Summary
Invasion and metastasis are major causes of death in cancer patients. Our research has uncovered a pathway that increases the invasive potential of tumour cells in vitro. We now aim to determine if the pathway is relevant in invasion and metastasis in clinically relevant models; how a drug targeting the pathway affects invasion and; the extent to which the pathway is active in human tumours. These studies may identify a new molecular target for anti-invasive drugs.
I am a cell biologist/geneticist focusing on understanding tumourigenesis. Cancer is a multigenic and complicated disease, involving interactions between the tumour and normal tissue. I use the genetically tractable model organism, the vinegar fly, Drosophila, to model cancer in situ and identify novel genes that drive cancer. My 5 year career plan is to use the Drosophila system to model cooperative tumourigenesis in epithelial and brain tissues and translate this to human cancer.