Microenvironmental Impact In The Treatment Of Acute Lymphoblastic Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$621,458.00
Summary
Acute lymphoblastic leukemia remains one of the leading causes of death in children and outcomes for adults with this disease remain poor. This project examines how manipulation of the environment where leukemia arises can be used to therpaeutic advancage. Acute lymphoblastic leukemia cells are highly dependent on the support provided by bone marrow cells but the mechanisms are not well understood. Disrupting signals from the bone marrow cells has potential as a therapeutic strategy.
Harnessing RNA Interference In Gene Therapy Vectors For ?-thalassaemia
Funder
National Health and Medical Research Council
Funding Amount
$719,188.00
Summary
There is an urgent need to develop safe and effective treatments for ?-thalassaemia. We anticipate that ?-globin-specific RNAi sequences will synergise with ?-globin transgene expression to achieve balanced ?-/?-globin ratio in a clinical setting. Given that one of the major issues with current gene therapy vectors is achieving high levels of expression, we believe this will be a more effective gene therapy strategy than ?-globin transgene expression alone.
Molecular Regulation Of Haematopoiesis In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$863,413.00
Summary
The blood forming system coordinates production of cells that confer immunity to infection, transport oxygen and assist blood clotting. When the molecular mechanisms that control these functions go awry, diseases including leukaemia and autoimmunity result. This research will define fundamental molecular regulators of blood cell production and function, assess their role in blood cell diseases and explore their potential to provide leads for development of new therapeutics.
A Newly Identified Role For 14-3-3zeta Protein In Thrombosis And Platelet Procoagulant Activity
Funder
National Health and Medical Research Council
Funding Amount
$556,327.00
Summary
Cardiovascular disease, including heart attack and stroke is the major cause of death globally, and is responsible for the death of 50,000 Australians each year. Platelet activation and blood coagulation play an important role in these diseases and we have discovered that a protein called 14-3-3 zeta is important in the processes that result in thrombosis. We are studying the mechanisms by which this protein contributes to life-threatening platelet activation with the aim of developing new and m ....Cardiovascular disease, including heart attack and stroke is the major cause of death globally, and is responsible for the death of 50,000 Australians each year. Platelet activation and blood coagulation play an important role in these diseases and we have discovered that a protein called 14-3-3 zeta is important in the processes that result in thrombosis. We are studying the mechanisms by which this protein contributes to life-threatening platelet activation with the aim of developing new and more effective anti-thrombotic drugs.Read moreRead less
Role Of Zeb2/Sip1 In Leukaemic Stem Cell Formation And Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$655,174.00
Summary
T-cell acute lymphoblastic leukaemia (T-ALL) results from the abnormal development of T cells that are an important cell type in the body's immune system. Although the prognosis for T-ALL has improved remarkably over the last decade, for one out of five T-ALL cases the underlying genetic defects remain unresolved and are refractory to current therapies. This project aims to use both novel mouse models and human patient cell lines to better understand this disease and discover novel targets for f ....T-cell acute lymphoblastic leukaemia (T-ALL) results from the abnormal development of T cells that are an important cell type in the body's immune system. Although the prognosis for T-ALL has improved remarkably over the last decade, for one out of five T-ALL cases the underlying genetic defects remain unresolved and are refractory to current therapies. This project aims to use both novel mouse models and human patient cell lines to better understand this disease and discover novel targets for fighting this disease.Read moreRead less
The Roles Of Retinoids And Their Receptors In Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$474,750.00
Summary
Haemopoietic stem cells (HSCs) are the most widely studied adult somatic stem cell. HSCs have huge potential, sustaining blood cell production throughout an individual's life. Cancers (leukaemias) and other disorders of the blood are largely treated by transplantation of HSCs. However, due to their rare occurrence, it is often difficult to obtain large numbers of HSCs for transplantation, especially from sources of HSCs such as cord blood. Furthermore, protocols requiring manipulation of HSCs, s ....Haemopoietic stem cells (HSCs) are the most widely studied adult somatic stem cell. HSCs have huge potential, sustaining blood cell production throughout an individual's life. Cancers (leukaemias) and other disorders of the blood are largely treated by transplantation of HSCs. However, due to their rare occurrence, it is often difficult to obtain large numbers of HSCs for transplantation, especially from sources of HSCs such as cord blood. Furthermore, protocols requiring manipulation of HSCs, such as gene therapy, have been largely unsuccessful, in part due to the lack of success in growing HSCs outside of the body. In such situations, therefore, determining culture conditions that would enable us to grow HSCs outside of the body are highly desirable. This application is based on the studies of CIA, who recently made the novel discoveries that the vitamin A derivative, all-trans retinoic acid (ATRA) has different effects in the regulation of blood cell production. ATRA is currently used in the treatment of acute promyelocytic leukaemia, as it enhances the maturation of the leukaemic cells. CIA has demonstrated that ATRA has the opposite effect on HSCs, with recent data strongly suggesting that ATRA induces the expansion of HSCs outside of the body. The studies outlined in this proposal seek to further define the mechanisms involved in these effects of ATRA and other vitamin A derivatives (collectively termed retinoids) in the regulation of blood cell production. The first specific aim will determine how retinoids expand HSCs. The second specific aim will explore the roles of the different RARs in the regulation of blood cell production. These studies have direct clinical relevance in improving protocols for transplantation and gene therapy of HSCs. Furthermore, insight gained into the roles of retinoids in blood cell production may also lead to the improvement of treatments of various types of blood disorders.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.
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
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.