Mechanisms Of Glucocorticoid Resistance In Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Glucocorticoids are extremely active drugs used in the treatment of childhood acute lymphoblastic leukaemia (ALL), yet a proportion of patients respond poorly to therapy and exhibit resistance at relapse. Clinically relevant mechanisms of glucocorticoid resistance are poorly understood, principally due to lack of appropriate experimental models. This project will reveal novel mechanisms of drug resistance in childhood leukaemia and lead to novel therapeutic strategies to improve outcome.
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.
Cellular And Molecular Determinants Of Preleukaemic And Leukaemic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$292,635.00
Summary
It has recently become evident that the formation, growth and relapse of many cancers is driven by a rare population of cancer stem cells (CSCs) that have the unique ability to propagate new tumours and are highly resistant to current therapies. However, which normal cells are transformed into CSCs is not known. We will take a potent cancer gene found in leukaemia, and switch it on and off in specific blood cells in mice to determine which healthy cells can be turned into leukaemic stem cells.
Acute myeloid leukaemia (AML) is a major health problem with only about one third of patients being cured. In addition therapies have changed little over the last 20 years. However there is optimism that with greater knowledge of the biochemical changes in AML that are caused by genetic mutations, more effective treatments will be developed. This project therefore aims to increase understanding of the biochemical interplay between two proteins called c-Cbl and Flt3 that are altered in AML.
An understanding of the way cells control their complex internal circuitry is relevant to diseases like cancer and leukemia. The main focus of this project is a cellular regulator we identified several years ago called BORIS. Normally dormant in all cells outside the male reproductive organs, BORIS is reactivated in many cancers. We will study the network of factors perturbed when BORIS becomes inappropriately active in cancer cells. Ultimately this project may lead to new treatments for cancer.
Identification Of Novel Targeted Therapies For JAK2-driven Leukemogenesis
Funder
National Health and Medical Research Council
Funding Amount
$392,717.00
Summary
Many leukemias are caused by particular signalling molecules becoming too active in blood cells. My research focusses on the molecules that are required by leukemic cells for their growth and survival. I will use mice that are prone to developing leukemia to study how these leukemias can be treated with drugs that block specific molecules. My goal is to discover new ways to treat leukemias that work better and have fewer side effects than current treatments.
I am a cancer cell biologist investigating molecular mechanisms of leukaemia cell resistance to chemotherapeutic drugs, and novel strategies for the management of high risk or relapsed disease. For these purposes I have developed orthotopic xenograft mode
Defining The Apoptotic And Therapeutic Activities Of Histone Deacetylase Inhibitors.
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
HDAC inhibitors (HDACi) are new chemotherapeutic drugs that kill tumors cells through a cell suicide process called apoptosis. We have now established a mouse model of human lymphoma whereby pro-apoptotic proteins have been eliminated or anti-apoptotic proteins overexpressed. We will identify the apoptotic proteins and pathways that are necessary for HDACi to kill cancer cells. Such information will lead to a more targeted or rational approach to chemotherapy using HDACi.
BIOLOGICAL STUDIES OF A NEW RECURRENT FUSION GENE FOUND IN T-CELL LEUKAEMIA
Funder
National Health and Medical Research Council
Funding Amount
$187,925.00
Summary
Chromosome translocation, in which breaks occur in two chromosomes and rejoin to form two new hybrid chromosomes, is a common genetic alteration in leukaemia. Translocations have been invaluable in identifying genes important in the development of leukaemia. The genetic consequence of translocation is either the deregulation of critical genes adjacent to the breakpoints or the formation of new hybrid genes with novel properties. We have identified the genes at the breakpoints of a T-cell leukaem ....Chromosome translocation, in which breaks occur in two chromosomes and rejoin to form two new hybrid chromosomes, is a common genetic alteration in leukaemia. Translocations have been invaluable in identifying genes important in the development of leukaemia. The genetic consequence of translocation is either the deregulation of critical genes adjacent to the breakpoints or the formation of new hybrid genes with novel properties. We have identified the genes at the breakpoints of a T-cell leukaemia translocation involving chromosomes 4 and 11. The chromosome 11 gene, NUP98, is known to be involved in two other translocations in acute myeloid leukaemia but not in T-cell leukaemia. The chromosome 4 gene RAP1GDS has not been previously shown to be involved in human cancer. This project seeks to understand how the fusion protein NUP98-RAP1GDS (NRG) plays a role in the origin of leukaemia.Read moreRead less
Activated Dendritic Cell Monoclonal Antibodies As Therapeutics To Prevent Graft Versus Host Disease
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
A New Therapy to Prevent Graft versus Host Disease in Bone Marrow Transplantation Bone marrow transplants often fail due to the immune reaction of the grafted donor cells against the patient (graft versus host disease). Current treatments to prevent this do not always work and have serious side-effects or other disadvantages.The immune reaction is induced by activated dendritic cells which are the primary stimulators of the body's defences against foreign invaders. We have developed antibodies i ....A New Therapy to Prevent Graft versus Host Disease in Bone Marrow Transplantation Bone marrow transplants often fail due to the immune reaction of the grafted donor cells against the patient (graft versus host disease). Current treatments to prevent this do not always work and have serious side-effects or other disadvantages.The immune reaction is induced by activated dendritic cells which are the primary stimulators of the body's defences against foreign invaders. We have developed antibodies in mice that react with human activated dendritic cells and prevent them from inducing immune responses in the test-tube. These antibodies are also likely to be effective in patients, but cannot be used in their present form because mouse antibodies induce an undesirable immune response in humans. We therefore plan to convert them to resemble human antibodies (antibody engineering). Antibodies that react with other types of cell in the body are already used to treat or prevent a variety of conditions, including graft versus host disease, but no one has developed a therapeutic antibody against activated dendritic cells. We are applying to the NHMRC for funding to engineer our antibodies and to test them in test tube experiments and also in mouse models of graft versus host disease. We also plan to study the changes in blood levels of activated dendritic cells in bone marrow transplnt patients. This will provide information on the best time to use our new therapeutic antibodies to prevent graft versus host disease. The aim of this grant application will have been achieved if, after three years, we have a new antibody ready for testing in bone marrow transplant patients.Read moreRead less