Molecular Analysis Of Myelodysplasia In The Nup98HoxD13 Mouse Model
Funder
National Health and Medical Research Council
Funding Amount
$351,502.00
Summary
Myelodysplastic syndrome is a preleukemic condition which is poorly understood and occuring at an increasing frequency. Unfortunately no targeted therapy exists. Two features of the disease are abnormal gene expression and abnormal cell death. We have a uniquely accurate model of this disease, and we plan to use it to investigate these two phenomena which will lead to greater understanding of the disease and new molecular targets for therapeutic agents to be developed and tested in our model.
The Role Of MOZ In The Development Of The Hematopoietic System, Spleen And Thymus
Funder
National Health and Medical Research Council
Funding Amount
$324,375.00
Summary
Current treatment of leukaemia in adults is unsatisfactory with the majority of patients dying. In the past most treatments for cancer have been empirical, that is a particular drug has been found to be effective by trial and error rather than a process of rational design. In order to improve the rate at which effective treatments for leukaemia are found it is necessary to understand how hematopoiesis is regulated and what the critical points are where things can go wrong, leading to cancer. Som ....Current treatment of leukaemia in adults is unsatisfactory with the majority of patients dying. In the past most treatments for cancer have been empirical, that is a particular drug has been found to be effective by trial and error rather than a process of rational design. In order to improve the rate at which effective treatments for leukaemia are found it is necessary to understand how hematopoiesis is regulated and what the critical points are where things can go wrong, leading to cancer. Some genes are commonly found to be mutated in leukaemia. Clearly these genes are involved in some key aspect of regulation of hematopoiesis. We are studying one of these genes, MOZ, which is mutated in acute myeloid leukaemia. The purpose of this grant is to determine what the normal function of this gene is. One of the most promising new treatments for leukaemia is directly targeting the regulation of gene expression inside the cell. MOZ is one of the proteins, which regulates gene expression in hematopoiesis and controls the differentiation of different types of blood cells. One of the possible effects of these new types of anticancer drugs is to accentuate the normal function of MOZ. However, at the moment we don't know what the normal function of MOZ is so it is impossible to test this prediction. If we know which pathways controlling blood formation MOZ is acting in it may be possible, in the future, to use this information to improve on the current anti cancer drugs in a more directed way than has been possible in the past.Read moreRead less
The Role Of A Phosphorylated Ser/Tyr Bidentate Motif In Leukemia And Myeloproliferative Disorders
Funder
National Health and Medical Research Council
Funding Amount
$279,254.00
Summary
The ability of a normal cell to survive and grow is subject to tight control. Cancer cells escape both these controls and survive and grow in an deregulated manner. Many therapies that are in clinical use or in pre-clinical development target the growth of cancer cells. While such an approach has the advantage of being highly effective in stopping the advance of cancer cell growth, it may allow the long-term survival of some cancer cells and increase the possibility that these cells will become ....The ability of a normal cell to survive and grow is subject to tight control. Cancer cells escape both these controls and survive and grow in an deregulated manner. Many therapies that are in clinical use or in pre-clinical development target the growth of cancer cells. While such an approach has the advantage of being highly effective in stopping the advance of cancer cell growth, it may allow the long-term survival of some cancer cells and increase the possibility that these cells will become resistant to drug treatment leading to disease relapse. On the other hand, therapies that target the survival of malignant cells would be expected to pull the rug from underneath cancer by killing the malignant cells regardless of whether they are growing or not. We have identified a signalling device in normal blood cells that controls both the growth and survival of cells. This device is in effect a switch with 2 components both of which are normally turned on and off. These 2 components are differentially wired to to the cell transmitting unique signals. Importantly, we have found that this switch is faulty in blood cancers and is permanently on in some leukemias promoting their prolonged life-span. Targetting specific components of this unregulated switch may provide new and improved approaches for the development of therapeutics in the treatment of leukemia.Read moreRead less
An Analysis Of The Lyn Tyrosine Kinase In The Regulation Of Hematopoiesis And Tumourigenesis.
Funder
National Health and Medical Research Council
Funding Amount
$381,000.00
Summary
The Lyn kinase is an enzyme that is involved in relaying information across the cell membrane. It is a member of a family of genes that have been implicated in tumour development. Lyn is expressed in blood cells and it is involved in a variety of immunological responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn protein (Lyn-deficient mice) and one that expresses an activated f ....The Lyn kinase is an enzyme that is involved in relaying information across the cell membrane. It is a member of a family of genes that have been implicated in tumour development. Lyn is expressed in blood cells and it is involved in a variety of immunological responses. To further our understanding of the role of this enzyme in the context of the whole animal, we have generated two strains of mice, one that is unable to make Lyn protein (Lyn-deficient mice) and one that expresses an activated form of the Lyn enzyme (Lyn-up mice). Our previous studies have shown that Lyn-deficient mice have enhanced blood cell formation (hematopoiesis) and develop white blood cell tumours with age, whereas Lyn-up mice show no propensity to develop tumours. In this study we will examine in detail the role that Lyn plays in blood cell formation and tumourigenesis, and we will identify the pathways that underlie the phenotypes in Lyn-deficient mice. On completion of these studies we will have catalogued the molecules and pathways regulated by Lyn, and have an understanding of how Lyn functions in regulating development of specific populations of blood cells, and in suppressing or promoting tumour development.Read moreRead less
Identification And Characterization Of Substrates Of Tyrosine Kinases Involved In Hematopoiesis And Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$241,527.00
Summary
The development and maintenance of tissues in mammals are tightly controlled and complex processes involving the growth, maturation and survival of vast numbers of cells of various types. In cancer, the cell's capacity to faithfully regulate these processes is diminished or lost. Many of the proteins that are essential for growth control are produced by an important class of genes called proto-oncogenes; literally, the prototypes of cancer-causing genes. Naturally occurring mutations in these ge ....The development and maintenance of tissues in mammals are tightly controlled and complex processes involving the growth, maturation and survival of vast numbers of cells of various types. In cancer, the cell's capacity to faithfully regulate these processes is diminished or lost. Many of the proteins that are essential for growth control are produced by an important class of genes called proto-oncogenes; literally, the prototypes of cancer-causing genes. Naturally occurring mutations in these genes have been identified in man and are likely to play a major role in the initiation and progression of distinct human malignancies. A significant number of proto-oncogenes are enzymes called protein tyrosine kinases (PTKs). Research has shown that the function of PTKs is to relay growth signals or other regulatory signals from the outer surface of the cell to specific target proteins inside the cell. These target proteins are needed to relay the signal to other target molecules and so on. This highly ordered process, involving a specific sequence of proteins, ensures that cells respond appropriately to a given signal. Our research focuses on identifying and studying the immediate targets of PTKs with the broad aim of understanding how PTKs control growth in normal and cancerous cells. We have recently developed a method that has enabled us to identify a new protein that may regulate the growth of blood cells. The research proposed here aims to extend our preliminary observations showing that the growth of specific types of blood cells is inhibited by this protein. We also plan to search for new targets of a PTK that is involved in leukemia. The findings of this research will provide important insight into how blood cells are regulated in health and disease.Read moreRead less
Leukaemia-cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of these is augmented activity of enzymes called tyrosine kinases including members of the Src family. One called Lyn has been implicated in several leukaemias as well as cancer. We have identified a novel mechanism of down-regulating this family of enzymes mediated by small proteins. These may allow us to develop novel therapeutics for cancer-leukaemia treatment.
Cancer is the result of multiple genetic errors, involving both the overactivity of growth-stimulating oncogenes and the loss of tumour suppressor genes. The identification of the genes in both of these categories is important if we are to understand and intervene in the disease. Tumour suppressors are the more difficult to identify, precisely because they are lost in cancer cells. Normally the task is extremely time consuming, tedious and expensive. We have developed a system which will provide ....Cancer is the result of multiple genetic errors, involving both the overactivity of growth-stimulating oncogenes and the loss of tumour suppressor genes. The identification of the genes in both of these categories is important if we are to understand and intervene in the disease. Tumour suppressors are the more difficult to identify, precisely because they are lost in cancer cells. Normally the task is extremely time consuming, tedious and expensive. We have developed a system which will provide a short-cut to the cloning of one such gene. We have started with the mouse version, which is lost in leukemic cells. We have mapped the gene to within a very small chromosomal region, and we have identified a biological effect which correlates with loss of the gene. Our next step is to combine these two approaches to clone the gene. Because these genes are always highly conserved between species, we will be able to quickly clone the corresponding human gene, the loss of which is very likely to be important in cancer of various types.Read moreRead less
Mechanisms Of Cytokine Independence During The Development Of Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$598,163.00
Summary
Signals from growth factors such as cytokines and hormones are required for cell survival. In their absence cells activate an in-built self-destruct process. Determining how cytokines regulate cell death will provide novel targets so that unwanted cells (like cancer cells) can be triggered to die and needed cells (such as brain cells) can survive.
INTERCEPT (Investigating Novel Therapy To Target Early Relapse And Clonal Evolution As Pre-emptive Therapy In AML): A Multi-arm, Precision-based, Recursive, Platform Trial
Funder
National Health and Medical Research Council
Funding Amount
$5,789,515.00
Summary
Acute myeloid leukemia is a rare and lethal blood cancer with limitless potential to evolve resistance. New technologies allow early detection of molecular 'fingerprints' of returning disease. We propose an international research team to conduct a multi-arm, precision-based platform trial aimed at increasing and extending the duration of patient response and survival using novel combination options. INTERCEPT will suppress and eradicate relapse before the patient becomes clinically unwell.
Targeting The EGFR And C-Met Tyrosine Kinase Receptors In Myeloproliferative Neoplasms
Funder
National Health and Medical Research Council
Funding Amount
$607,559.00
Summary
We propose that in the blood disorders called Myeloproliferative Neoplasms (MPN) there are important changes that affect the function of receptors expressed on the surface of blood cells. These changes will perturb blood cell production and may be able to be targeted effectively with drugs. We will test this using laboratory-based and mouse models of MPN, together with specific drugs that are currently in the clinic, and that inhibit the activity of the key receptors involved. This approach can ....We propose that in the blood disorders called Myeloproliferative Neoplasms (MPN) there are important changes that affect the function of receptors expressed on the surface of blood cells. These changes will perturb blood cell production and may be able to be targeted effectively with drugs. We will test this using laboratory-based and mouse models of MPN, together with specific drugs that are currently in the clinic, and that inhibit the activity of the key receptors involved. This approach can be rapidly translated to clinical trial.Read moreRead less