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.
MINIMAL RESIDUAL DISEASE IN ACUTE LYMPHOBLASTIC LEUKAEMIA
Funder
National Health and Medical Research Council
Funding Amount
$455,204.00
Summary
This project will study the extremely small numbers of leukaemic cells which are found in patients who are apparently healthy, but which sometimes lead to relapse. Very sensitive methods for measuring and studying low levels of leukaemic cells will be developed and used. To develop new better treatments in the long term, we will study why current treatment sometimes fails to eradicate the leukaemia, leading to patients relapsing. Clinicians currently need to obtain samples of bone marrow to asse ....This project will study the extremely small numbers of leukaemic cells which are found in patients who are apparently healthy, but which sometimes lead to relapse. Very sensitive methods for measuring and studying low levels of leukaemic cells will be developed and used. To develop new better treatments in the long term, we will study why current treatment sometimes fails to eradicate the leukaemia, leading to patients relapsing. Clinicians currently need to obtain samples of bone marrow to assess leukaemia, and the research will show whether this needs to be continued, or whether, with sensitive tests, samples of blood can be used instead. The study will involve collaboration with clinicians throughout Australia and overseas.Read moreRead less
CXCR4 Antagonists In Acute Lymphoblastic Leukemias In NOD/SCID Mice
Funder
National Health and Medical Research Council
Funding Amount
$505,500.00
Summary
Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and a major cause of death in children. Although ALL is usually responsive to chemotherapy, about 25% of children and 65% of adults with ALL develop a relapse of their disease. The majority of these patients will die of leukemia. New approaches to the treatment of ALL are necessary to obtain cures for these patients. We have identified stromal-derived factor (SDF)-1 as a major regulator of ALL cell growth and survival ....Acute lymphoblastic leukemia (ALL) is the most common form of childhood cancer and a major cause of death in children. Although ALL is usually responsive to chemotherapy, about 25% of children and 65% of adults with ALL develop a relapse of their disease. The majority of these patients will die of leukemia. New approaches to the treatment of ALL are necessary to obtain cures for these patients. We have identified stromal-derived factor (SDF)-1 as a major regulator of ALL cell growth and survival. It is currently the only known factor that significantly stimulates the growth-survival of cells from the majority of patients with ALL. Specific antagonists of the SDF-1 receptor, CXCR4, are available. Depriving ALL cells of SDF-1 by the use of these antagonists provides a radically new approach for the treatment of ALL. CXCR4 antagonists also increase the susceptibility of ALL cells to cytotoxic drugs. The mechanisms by which SDF-1 promotes ALL cell growth and survival are not known but appear to be largely due to synergistic interactions with other molecules that have little or no effect on their own. Knowledge of the underlying mechanisms of action of SDF-1 and the factors with which it synergises will facilitate for the further development of this approach. This project will examine the modulation of the expression of proteins that regulate ALL cell growth and survival by CXCR4 antagonists, providing insights into how CXCR4 antagonists work. This project will also extend our encouraging data obtained using tissue culture to an animal model of leukemia. The antagonists will be tested in isolation and in combination with currently used chemotherapy agents. It is expected that CXCR4 antagonists will inhibit the growth of ALL cells and increase their sensitivity to chemotherapy agents in the animal model as we have seen in laboratory culture. The addition of CXCR4 antagonists to current treatment protocols is expected to significantly improve the outcome for patients.Read moreRead less
The Use Of Minimal Residual Disease Detection To Improve Treatment Outcome In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the c ....Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the cancer burden is at a low level, has a high likelihood of improving patient survival. The failure to respond well to treatment is assessed by a novel molecular genetic technique developed in our laboratory that can detect and quantitate very low levels of residual leukaemia with great sensitivity and specificity. The major goal of this project is to conduct a clinical trial in which this testing procedure is used at an early stage of treatment, and patients who have a bad result on this test, will be given more intensive treatment to see if this improves survival rates. In addition, the project is also directed towards investigating a range of genes known to have a role in drug detoxification. A number of naturally occurring variations exist for these drug metabolising genes and there is evidence suggesting that specific variations or patterns may influence a cancer's response to treatment. We will therefore examine the genetic patterns present in a large cohort of leukaemias and correlate these patterns with response to treatment. It is anticipated that these studies will help define the most appropriate treatment strategies for children with leukaemia. This project therefore has major implications for the therapeutic management of children with leukaemia and has the potential of contributing directly to the improved survival of this most common of childhood cancers.Read moreRead less
Antagonists Of P38 MAPK As Therapeutics For Acute Lymphoblastic Leukemia.
Funder
National Health and Medical Research Council
Funding Amount
$521,961.00
Summary
New therapies are needed to treat patients with leukemia. Moving leukemic cells into the blood reduces their growth and increases the effects of chemotherapy. Currently we cannot move leukemic cells into the blood without moving normal blood forming cells, making them more sensitive to chemotherapy. We have identified a drug that only affects leukemic cell movement. This study will examine the potential of this drug to treat leukemia.
The Use Of Minimal Residual Disease Detection To Improve Treatment Outcome In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$374,625.00
Summary
Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Evidence obtained by ourselves and others, suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of altern ....Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Evidence obtained by ourselves and others, suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the cancer burden is at a low level, has a high likelihood of improving patient survival. In this regard, we have recently developed a novel molecular genetic technique that can detect and quantitate very low levels of residual leukaemia with great sensitivity and specificity. This technique is ideally suited for use in the routine clinical setting, and as a result of this development, we have now established a clinical trial (ANZCCSG Study VIII) in which patients who have a bad result on this test, will be given more intensive treatment to see if this improves survival rates. A number of research questions will also be addressed in this trial including whether the level of residual leukaemia at the end of therapy is able to predict future relapse that would otherwise not be suspected. It is anticipated that the clinical trial will help define the most appropriate treatment strategies for children with leukaemia. This project, which is at the forefront of such studies worldwide, has major implications for the therapeutic management of children with leukaemia and has the potential of contributing directly to the improved survival of this most common of childhood cancers.Read moreRead less