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.
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.
New Compounds For Tailored Therapy Against MLL-rearranged Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$326,401.00
Summary
Some of the worst leukaemia survival rates are found in children and adults whose leukaemias display abnormalities of the MLL gene and alternative therapies are therefore urgently required for these patients. The aim of this project is to develop new compounds that specifically inhibit this abnormal gene and in turn inhibit the growth of these cells in the patient. In this way we hope to provide new and more effective therapies for patients affected with this aggressive type of leukaemia.
Genetic Polymorphisms In Genes Controlling Innate Immunity As Risk Factors For Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$241,500.00
Summary
For some time now, researchers have speculated that the development of childhood leukaemia is related to exposure to an infectious agent. However, a causal pathogen is yet to be identified. Recent studies have shown that the initial recognition of microbes as they enter the human body is determined by a group of receptors, toll-like receptors (TLRs), which selectively bind to essential components of these pathogens. This process allows the body to respond immediately to microbial invasion; a pro ....For some time now, researchers have speculated that the development of childhood leukaemia is related to exposure to an infectious agent. However, a causal pathogen is yet to be identified. Recent studies have shown that the initial recognition of microbes as they enter the human body is determined by a group of receptors, toll-like receptors (TLRs), which selectively bind to essential components of these pathogens. This process allows the body to respond immediately to microbial invasion; a process which is vital during early childhood, when clonal expansion of antibodies and other host defences is inadequate. It is becoming increasingly apparent that this innate immune response is not just the first line of defence but a necessary event for the development of an adaptive immune response. We propose that the innate immune system of children carrying TLR gene variants may be less effective at detecting the presence of microbial pathogens in the environment. We hypothesize that by dampening the stimulation of innate immunity in early childhood, TLR gene variants may indirectly cause a dysfunction in the maturation of a child's immune system and increase the chance of a pre-leukaemic clone emerging, leading to the development of childhood leukaemia.Read moreRead less
Genome-wide Epigenetic Analysis Of Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$410,469.00
Summary
Of all cancers in children, Acute Lymphoblastic Leukaemia is the most common. To date, the causal mechanism(s) for leukaemia in children remain unclear. Although 5-year event-free survival rates are relatively high (up to 80%) it is still unclear why children expected to survive with a good prognosis, succumb to the disease. Therefore, there is still a need to further refine current diagnosis and prognosis parameters that will together lead to improved outcomes to children with leukaemia.
The Role Of Microtubule Composition In The Efficacy Of Antimicrotubule Agents In Paediatric Malignancy
Funder
National Health and Medical Research Council
Funding Amount
$173,380.00
Summary
To enhance the management of both childhood and adult cancers improved understanding of the processes responsible for tumour aggressiveness and drug resistance are required. Microtubules are important structural components of cells which are crucial for normal cell division. This makes microtubules excellent targets for anticancer drugs which can disrupt microtubules and kill cancer cells. This proposal will identify whether the microtubule composition of a tumour cell will predict for the aggre ....To enhance the management of both childhood and adult cancers improved understanding of the processes responsible for tumour aggressiveness and drug resistance are required. Microtubules are important structural components of cells which are crucial for normal cell division. This makes microtubules excellent targets for anticancer drugs which can disrupt microtubules and kill cancer cells. This proposal will identify whether the microtubule composition of a tumour cell will predict for the aggressiveness of certain cancers, and whether this influences which tumours will respond to the vinca alkaloids. The vinca alkaloids are an important class of natural product drugs which disrupt microtubules and are particularly effective in the treatment of adult and childhood cancers. Unfortunately, some cancer cells fail to respond to this treatment due to the development of drug resistance. This proposal addresses vinca alkaloid resistance in children?s cancer and will determine why certain cancer cells fail treatment. Furthermore, this study will identify the role of certain components of microtubules that appear to be related to drug resistance in leukaemia and neuroblastoma cells and whose role is unknown. Chemotherapeutic drugs, such as the vinca alkaloids, are important in the treatment of cancer and knowledge about their interaction with their cellular target will improve the design of new drugs and treatment outcome.Read moreRead less
Improving Treatment Outcome In Paediatric Acute Lymphoblastic Leukaemia By Minimal Residual Disease Detection And Pharmacokinetics
Funder
National Health and Medical Research Council
Funding Amount
$609,759.00
Summary
The main objective of this project is to make substantial improvements in the treatment of patients with childhood leukaemia by greater use of molecular diagnostics to measure minimal residual disease (MRD) and pharmacokinetic testing to determine the effectiveness of a key chemotherapy drug (PEG-L-Asparaginase) in Australian patients enrolled on an international clinical trial which has been designed to reduce the incidence of both relapses and long term side-effects.
Transcriptional Complexes In Haematopoiesis And T-cell Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Childhood T-cell leukemias have a poor prognosis for recovery. We are determining, with atomic level precision, how the proteins LMO2 (also linked to prostate and other cancers) and Tal1, and their binding partners contribute to both normal blood cell development and T-cell leukemia. With this information we are developing reagents that can be used to disrupt disease-causing complexes, and which will lead towards the development of new, specific, therapeutics for leukemias and other cancers.
A New Model Of T Cell Lymphoma Induced By An Ets Transcription Factor
Funder
National Health and Medical Research Council
Funding Amount
$679,091.00
Summary
The identification of leukaemia-causing genes is crucial as once these are found new specific drugs can be developed. This is best exemplified by the new drug, Gleevec, that inhibits a leukaemia-causing gene in myeloid leukaemia. This has allowed a large reduction of high chemotherapy treatment but has induced remission in around 80% of patients. This proposal has identified a novel leukaemia-causing gene for T cell leukaemia. Therefore, new specific drugs can now be made to inhibit it.