The Regulation And Role Of Puma And P53 In IL-3 Withdrawal Induced Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$527,683.00
Summary
It is the ultimate fate of most of our cells to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . When cell death fails to occur, abnormal cells can accumulate and lead to cancer. Signalling from growth-factors is required for many cell types to survive. When these signals are lost, the cells activate their cell death pathways. It is a hallmark of cancer cells that they ha ....It is the ultimate fate of most of our cells to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . When cell death fails to occur, abnormal cells can accumulate and lead to cancer. Signalling from growth-factors is required for many cell types to survive. When these signals are lost, the cells activate their cell death pathways. It is a hallmark of cancer cells that they harbour mutations in cell death genes and their dependence on growth factors for survival is diminished or lost. The genes of the apoptosis pathway function either to promote or inhibit cell death. Some genes in the apoptosis pathway allow apoptosis to proceed rapidly, but do not decide the fate of the cell. Other genes are required for a cell to commit to die, and if they are mutated then a functional cell, that is capable of proliferating, survives. This is a crucial distinction because it is only the genes that decide cell fate that can act as cancer genes, and are valid targets for therapy. We have identified one particular gene, Puma, as an important regulator of cell survival. Without this gene, cells survive longer without growth-factor and, importantly, can proliferate when growth factor is restored. Understanding how this gene functions and is regulated will contribute to our understanding of the gene mutations that lead to cancer and may identify valid targets for cancer therapy. In our model we use growth factor dependent cell lines derived from mice lacking particular genes in the cell death pathway, including Puma. These cells proliferate in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn. Using this system, we will determine how Puma is able to induce cell death, what other genes are required to regulate this process and how loss of Puma function may contribute to cancer development.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.
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.
Develop New Approaches To Cancer Diagnosis And Treatment
Funder
National Health and Medical Research Council
Funding Amount
$4,000,000.00
Summary
Apoptosis is the dominant focus of our planned studies, because its impairment is both a critical step towards malignancy and a barrier to effective treatment. Arguably, the laboratory heads within our division and our collaborators from the Structure Biology Division at WEHI constitute the world’s strongest group with this focus. Our accumulated experience in this field from its renaissance in 1988 and the many unique materials they have created superbly position us to answer the fundamental qu ....Apoptosis is the dominant focus of our planned studies, because its impairment is both a critical step towards malignancy and a barrier to effective treatment. Arguably, the laboratory heads within our division and our collaborators from the Structure Biology Division at WEHI constitute the world’s strongest group with this focus. Our accumulated experience in this field from its renaissance in 1988 and the many unique materials they have created superbly position us to answer the fundamental questions and translate them into new therapeutic approaches. Our team’s second focus, the links of stem cells to cancer, is also of great importance, because the rare stem cells in the tumour may dictate therapeutic outcome. This Fellowship aims to addresses fundamental issues with enormous potential for medicine. It builds on productive ongoing research by a team with diverse complementary expertise, a record of effective interaction, high momentum and a history of path-breaking discoveries. I plan to maintain and further develop our Division (the Molecular Genetics of Cancer Division at WEHI) as one of the strongest teams for cancer research and development of cancer therapies in the world. Our division contains several laboratories that are highly interactive and complimentary in their approaches and research interests. I plan to strengthen the already highly productive laboratories in our division and to develop some new ones (see below under ‘proposed team’). I plan to increase work of our division to also include studies on other solid tumours (e.g. colon cancer, lung cancer, prostate cancer). This Fellowships aims to greatly enhance cancer research and hopefully also clinical practice in Australia. This should enhance the reputation of Australia as a country with recognized excellence in medical research and clinical practice. I am also confident that our division will continue to educate outstanding PhD graduates and postdoctoral fellows who will in due course become independent researchers and develop into future leaders in medical research in Australia and-or overseas.Read moreRead less
Characterizing The Cancer Stem Cell Population In Human Acute Myeloid Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$380,665.00
Summary
At the root of many cancers are rare cells that sustain a tumour’s ability to grow and spread. These rare cells, termed “cancer stem cells”, are poorly understood and unfortunately are not eliminated by most current cancer therapies. Thus, after a course of chemotherapy that has eradicated the bulk of the tumour, these rare cells can persist and allow the disease to return. The aim of this proposal is to better characterize cancer stem cells so that improved therapies can be devised.
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.
Chemotherapy causes a massive depletion of blood-producing cells in the bone marrow. This results in a condition known as myelosuppression that has many harmful side effects for cancer patients. Our aim is to develop a safe and inexpensive approach that will specifically protect the blood-producing cells from chemotherapy but leave the cancer cells sensitive. If this treatment shows significant benefits in mouse models of cancer then the establishment of clinical trials will be initiated.
The Role Of Hox Genes In Myeloid Cell Development And Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$591,286.00
Summary
The transformation of normal white blood cells into leukaemic cells occurs as a result of changes to the genes of those cells. These changes are often characteristic of particular cancers and carry diagnostic and prognostic significance. This work will determine how critical some of the typical genetic changes of leukaemia are to the occurrence and persistence of cancer. Importantly, we will determine whether targeting these changes can provide new and effective approaches to treatment.
Determining The Prerequisites For The Achievement Of Treatment-free Remission In Chronic Myeloid Leukaemia To Facilitate The Development Of New Therapeutic Approaches With Curative Intent
Funder
National Health and Medical Research Council
Funding Amount
$1,318,775.00
Summary
Chronic myeloid leukaemia (CML) can usually be treated effectively with long-term tyrosine kinase inhibitor (TKI) therapy. Remarkably, rare patients who achieve excellent responses can stop treatment altogether without relapsing. Detailed studies of these patients in terms of their genetic background, the biology of their leukaemia and their immune response may help us understand how this is possible, leading to new therapeutic approaches to make treatment-free remission more widely achievable.