Improving Patient Outcomes In Leukaemia By Targeting Cancer Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$294,763.00
Summary
Blood cancers such as acute myeloid leukaemia (AML) are among the most deadly types of cancer and new treatments are desperately needed to improve patient’s survival in these diseases. AML cancer-causing stem cells survive by turning on immortalization programs and we hope to specifically kill these AML stem cells by blocking these crucial pathways. This includes things that control the way the cells divide and the way they respond to genetic damage as well as other novel pathways.
Understanding Autophagy In Haematopoiesis And Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$500,813.00
Summary
Blood cancers such as leukaemia are among the most deadly types of cancer and new treatments are desperately needed to improve survival. We have identified a new pathway that is activated when cells undergo stress. This pathway controls the survival of normal blood cells and also appears to be very important in the way cancer cells respond to chemotherapy. We will characterize this pathway in normal blood cells and use this information to develop new treatments to target and eliminate the leukae ....Blood cancers such as leukaemia are among the most deadly types of cancer and new treatments are desperately needed to improve survival. We have identified a new pathway that is activated when cells undergo stress. This pathway controls the survival of normal blood cells and also appears to be very important in the way cancer cells respond to chemotherapy. We will characterize this pathway in normal blood cells and use this information to develop new treatments to target and eliminate the leukaemia cells.Read moreRead less
Modern chemotherapies are designed to exert maximal effect on tumour cells while having minimal side-effects on normal cells. Remarkable advances in our understanding of the molecular biology of cancer has provided possible avenues for more successful targeted cancer treatments. Several crucial interactions between cancer-specific proteins called oncoproteins , occur largely in tumour cells and thus provide ideal targets for intervention. The proposed project is to develop a model system for a t ....Modern chemotherapies are designed to exert maximal effect on tumour cells while having minimal side-effects on normal cells. Remarkable advances in our understanding of the molecular biology of cancer has provided possible avenues for more successful targeted cancer treatments. Several crucial interactions between cancer-specific proteins called oncoproteins , occur largely in tumour cells and thus provide ideal targets for intervention. The proposed project is to develop a model system for a target specific therapy of leukaemia cells by blocking the interactions between oncoproteins. Moreover, the ability to isolate specific blockers of particular protein-protein interactions provides an opportunity to unravel complex genetic pathways in mammalian systems, which are relatively intractable by other analyses. The dissection of pathways using specific blockers may also provide a useful avenue for identifying new drug targets. We have chosen to target particular interactions involving one known oncoprotein in the search for specific inhibitors. A genetic selection will be used to identify random, constrained peptide sequences which are capable of blocking these interactions and which do not interfere with other interactions involving the oncoprotein. This technique allows one to select for or against specific blockers of known interactions from a library containing millions of candidate drug leads in baker's yeast cells. This procedure will be most suitable for high through-put drug screening projects. The validity of this approach to the identification of new peptide drug leads will be finally established in vivo using transgenic models of oncoprotein-dependent cancer in mice.Read moreRead less
Is Hypoxia Inducible Factor 2 The Trigger Of The Angiogenic Switch And A Driver Of Disease Progression In Myeloma?
Funder
National Health and Medical Research Council
Funding Amount
$605,096.00
Summary
Multiple myeloma (MM) is a fatal cancer of plasma cells (PC). PC migrate to the bone marrow, which compared with other organs is low in oxygen (hypoxic). In response to this hypoxia, the cancer cells turn on the expression of genes called hypoxia-inducible factors (HIF). HIFs activate the expression of genes that encourage blood vessel formation, which in turn stimulates greater tumour growth and disease progression. This proposal will investigate the role of HIFs in the progression of MM.
Determining The Transcriptional Programme Of A Leukaemogenic Transcription Factor In Normal And Leukaemic Cells
Funder
National Health and Medical Research Council
Funding Amount
$643,958.00
Summary
Leukaemic (blood cancer) cells develop from immature blood cells by inappropriate expression of genes. These genes are also those that are required for normal blood production in the embryo. Gene expression during normal blood development is tightly controlled. However in leukaemia, these genes are expressed at inappropriate stages of blood development. We will investigate whether leukaemic cells adopt features of embryonic blood stem cells to express genes that convert normal cells into abnorma ....Leukaemic (blood cancer) cells develop from immature blood cells by inappropriate expression of genes. These genes are also those that are required for normal blood production in the embryo. Gene expression during normal blood development is tightly controlled. However in leukaemia, these genes are expressed at inappropriate stages of blood development. We will investigate whether leukaemic cells adopt features of embryonic blood stem cells to express genes that convert normal cells into abnormal cells.Read moreRead less
Klf5 Function In Normal And Leukaemic Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$609,924.00
Summary
Acute Myeloid Leukaemia (AML) is a devastating disease that affects both children and adults. New treatments that target particular genetic abnormalities are urgently needed. We have identified KLF5 as a gene that may control blood cell maturation. In AML patient samples we have found alterations of the KLF5 gene that may suppress its activity and contribute to the formation of leukaemia. These leukaemias may be good candidates for treatment with new drugs called methyltransferase inhibitors.
Characterisation Of CBF Acute Myeloid Leukaemia By MicroRNA Profiling
Funder
National Health and Medical Research Council
Funding Amount
$118,956.00
Summary
Recent studies have demonstrated the existence of small pieces of previously undescribed genetic material, known as microRNAs (miRNAs), which are thought to have critical functions across various biological processes and regulatory pathways in cells. This project aims to examine the role of these miRNAs in the development of abnormal cellular proliferation that leads to leukaemia, by examining the expression of all known miRNAs in the abnormal cells of our patients with leukaemia.
Regulation Of Megakaryocyte And Platelet Survival In Malignancy
Funder
National Health and Medical Research Council
Funding Amount
$536,914.00
Summary
In this grant we will investigate how blood cells called platelets are produced in normal conditions and during disease. Platelets are blood cells that stop us from bleeding when we get a cut. When too many platelets accumulate, there is an increased risk of blood clots forming. This project grant will help us learn how platelet numbers swell in response to some blood and ovarian cancers, and the mechanisms that control cell death in platelets and the cells that produce them.
Dissecting The Role Of The IL-3 Receptor Alpha Subunit And Beta-catenin In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
Leukaemia is a devastating form of blood cancer affecting both young and old. We aim to understand the mechanisms of uncontrolled cell growth associated with acute myeloid leukaemia. We focus on the role of key growth regulators that are abnormally active in the critical leukaemia stem cells. Understanding the biological and molecular properties of these cells is of considerable importance for development of the next generation of leukaemia therapies.
Molecular And Cellular Mechanisms Of Skeletal Disease Mediated By Plasma Cell Dyscrasias
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in add ....Osteolytic and osteosclerotic lesions of bone are common sequelae of primary and secondary bone cancers, including cancers of hematological origin. There is now strong evidence that tumor cells perturb the local balance between bone resorption and formation, and in cases of osteolysis, cause increased osteoclast (OC)-mediated bone resorption without a matching amount of bone formation. This proposal arises from our extensive clinical and basic science experience with multiple myeloma (MM) in addition to other skeletal tumors, and our strong background in both OC and osteoblast biology. MM is a hematological malignancy characterised by plasma cell dyscrasia, which typically causes progressive and severe destruction of the skeleton, with accompanying bone pain, fracture and finally, hypercalcaemia of malignancy. Two related diseases, MGUS and POEMS, have been chosen for study because of their key similarities and differences with MM, and are likely to shed new light on the activities of MM in the bone. MGUS does not cause identifiable bone defects, whereas POEMS can give rise to both osteolytic and osteosclerotic lesions. Comparison of these conditions will uniquely enable us to examine why these seemingly related neoplasms are able to mediate disparate skeletal disease states. Primarily, and since there are few curative therapies for MM at present, our proposed studies are designed to identify targets for therapy that will treat the most serious manifestation of this disease, namely its destruction of bone tissue.Read moreRead less