The Biology And Clinical Manifestations Of Chronic Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$440,583.00
Summary
I am a haematologist studying the biology and clinical manifestations of chronic myeloid leukaemia with particular reference to the dynamics of response to kinase inhibitor therapy and the causes and clinical management of suboptimal response and drug res
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
Exploring The Role Of The Bcl-2 Family In Haematopoiesis And Haematopoietic Malignancy
Funder
National Health and Medical Research Council
Funding Amount
$190,980.00
Summary
Chronic Lymphocytic Leukaemia and Non-Hodgkin Lymphoma comprise the majority of blood cancers and are both disease in which the cell death pathway plays a vital role in both the development of the cancer cell and the resistance to chemotherapy. This project aims to examine the mechanisms of cancer in these tumours focussing on lymphoid cancers, and examine the role of new treatments targeting this pathway.
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.
The Targeting Of Flt3, C-Kit And Src As Therapies For C-Cbl-associated Myeloid Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$535,416.00
Summary
Most leukaemias are incurable so it is important to find new treatments. For this to occur it is essential that the mutated genes causing leukaemia are identified. We have generated a mouse with a mutation in a gene, c-Cbl, that promotes the activation of a number of proteins involved in leukaemia development. By treating c-Cbl mutant mice with drugs that target these proteins we intend to identify the most effective treatments for human leukaemias associated with c-Cbl mutations.
Genetic Analysis Of Drug Resistance In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Treatment for childhood leukaemia fails in approximately 25% of children owing to resistance to the drugs being used. Our recent evidence suggests that only a few rare leukaemic cells are initially resistant at the commencement of treatment. This project aims to isolate these rare cells and to look for genetic changes in them which might account for their resistance. Hopefully an understanding of the genetic basis for drug resistance will lead to better means of overcoming it.
Development Of A Treatment Algorithm For Kinase Inhibitor Therapy In CML.
Funder
National Health and Medical Research Council
Funding Amount
$527,761.00
Summary
Chronic myeloid leukaemia has become a highly treatable condition since targeted therapy became available. There are now 3 highly effective drugs available, imatinib, nilotinib and dasatinib. We are developing drug sensitivity assays that can be used to predict response to these 3 drugs. We propose that these assays could be used to individualise therapy to ensure that the optimal drug can be provided for each patient from diagnosis to provide a cost-effective customized approach to therapy.
Niche Regulation Of Normal And Malignant Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$622,655.00
Summary
Hematopoietic stem cells (HSC) reside in the bone marrow (BM) and make all the cells of the blood system. We study molecules in the BM regulating normal HSC to helping them survive chemotherapy. This means cancer patients should suffer less side-effects from their therapy. Some of these molecule also help leukaemia stem cells (LSC) resist chemotherapy. Inhibitors may a) reduce patient mortality caused by chemotherapy and b) sensitise LSC to chemotherapy enabling long-term cure.