I am a cancer molecular and cell biologist determining the mechanisms of anticancer drug action and resistance in both childhood and adult malignancies. My research involves the development and investigation of both in vivo and in vitro models of resistan
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
Genetic Dissection Of The Gp130 Signalling Network; Implications In The Initiation Of Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$447,500.00
Summary
Stomach cancer is a major health problem in the world. It is the second most common cancer and the second leading cause of death from cancer, behind lung cancer. In fact, approximately 10% of all new reported cancer cases world-wide are stomach cancer. The risk of stomach cancer increases with age, with risk rising progressively and peaking at about 60 years of age. Men are affected twice as often as women Like all cancers, stomach cancer results from the progressive acquisition of mutations in ....Stomach cancer is a major health problem in the world. It is the second most common cancer and the second leading cause of death from cancer, behind lung cancer. In fact, approximately 10% of all new reported cancer cases world-wide are stomach cancer. The risk of stomach cancer increases with age, with risk rising progressively and peaking at about 60 years of age. Men are affected twice as often as women Like all cancers, stomach cancer results from the progressive acquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations which predispose individuals to stomach cancer accumulate in the epithelial cells that provide the lining to the stomach. The progression of stomach cancer proceeds through a number of distinct anatomical stages which can be easily recognised by pathologists. Mutations in a number of genes (known as Kirsten-ras, p53) are commonly found in stomach tumours. Moreover, some of the mutations are highly associated with distinct stages of tumour development. As yet, however, we have no real insights into how these mutations cooperate with each other to produce full-blown (malignant) stomach cancer. In our proposal, we are aiming to establish stomach cancer in mice. Our approach will be to use an existing animal model which is predisposed to stomach cancer. We will progressively introduce mutant genes into stomach epithelial cells and study how they cooperate with each other to produce benign, and ultimately, malignant tumours in the stomach of mice. This will help us to understand which mutant genes are required for each stage in tumour development and may provide more rational approaches to stomac cancer screening and treatment.Read moreRead less
Molecular Targeting To Telomerase And Cancer Cell Immortality By A Novel Inhibitor
Funder
National Health and Medical Research Council
Funding Amount
$430,812.00
Summary
Infinite growth of cancer cells is a hallmark of cancer. Telomerase is required for cancer cell immortality. Inhibition of telomerase may thus offer an opportunity to stop cancer cells. We have identified an inhibitor of telomerase. This project will study the mechanisms of action of the novel inhibitor, investigating how to control cancer cell immortality as a baseline for more applied anti-cancer therapeutic studies.
Functional Genomics Approaches To Define New Drug-targets For Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$374,797.00
Summary
Cancer is a deadly disease that results from the accumulation of genetic mistakes (mutations) that encourage cells to divide and spread. There are some key mutations that occur in many different types of cancer. My project aims to exploit this common blueprint to design drugs that will selectively kill cancer cells, while leaving normal cells unharmed. We will identify new drug targets for the treatment of breast, colon and lung cancer and assess these targets in a variety of model systems.
One of the hallmarks of cancer cells is their ability to divide and multiply in an uncontrolled manner. Specific proteins that make up the skeleton of cells (cytoskeleton) play an important part in the cell division process and as such make extremely important targets for anticancer therapy. Our research is developing ways to best target cell division proteins so that we can make drug resistant cancer cells sensitive to chemotherapy.
Synthetic Analogues Of The Actinomycin, Quinamycin And Nogalamycin Groups Of Antitumour Antibiotics
Funder
National Health and Medical Research Council
Funding Amount
$376,433.00
Summary
The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar ....The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar scenario in the treatment of adults with leakaemias and non-Hodgkins lymphomas. The underlying cause of drug resistance is the genetic instability of cancer cells which results in tumours that are heterogeneous, making it almost inevitable that a cancer cell will arise that is resistant to treatment. There are many mechanisms of resistance, some of which are peculiar to particular drug types, some are permeability barriers and some involve genetic deregulation of the biochemistry of cell death. One way of subverting resistance is by the use of drugs whose mechanism of action is novel so that the tumour is challenged to devise a new defense. Here, we are attempting to develop synthetic analogues of a class of naturally- occurring antitumour antibiotic whose mechanism of action is unusual but which has not been exploited by medicinal chemists because of the difficulty of the chemistry involved. These antibiotics work by binding to DNA and inhibiting the first step in the process whereby genes are turned into proteins. We have designed compounds that are chemically accessible that our preliminary work suggests mimic the DNA-binding and biological properties of the natural antibiotics. The proposed work will enable us to evaluate whether this new class of agent has experimental antitumour activity, particularly amongst drug-resistant tumours.Read moreRead less
The MYB gene as a model for global transcriptional regulation: stopping, starting and looping. This project will study how transcriptional elongation controls the MYB gene, a key regulator of normal and cancerous growth and regulation. There are three major benefits that are likely to flow from the proposed research It will strengthen research in new and important areas of transcriptional regulation, by building research capacity in Australia in the area of gene expression, particularly with res ....The MYB gene as a model for global transcriptional regulation: stopping, starting and looping. This project will study how transcriptional elongation controls the MYB gene, a key regulator of normal and cancerous growth and regulation. There are three major benefits that are likely to flow from the proposed research It will strengthen research in new and important areas of transcriptional regulation, by building research capacity in Australia in the area of gene expression, particularly with respect to transcriptional elongation and long-range regulation. It will highlight a new approach to the therapeutic targeting of MYB in cancer: data generated from this research may enable us to target MYB expression in a range of cancers including breast cancer by inhibiting transcriptional elongation. And it will provide training in advanced molecular biology to postdoctoral scientists and students.Read moreRead less
A Preclinical Model Of Relapse In Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$573,515.00
Summary
Leukaemia is the most common type of cancer in children but resistance to therapy continues to be a significant problem. This project will investigate the biology of drug-resistance and relapse using a mouse model that replicates the human disease. We hope to identify novel therapeutic targets that can be used in combination with existing therapies to improve outcomes in this disease. We also hope to identify markers that can be used to screen for patients at increased risk of relapse.