Genetic Analysis Of Cell Death Pathways, Drug Resistance And Oncogenic Co-operativity In IL-3 Dependent Cell Lines
Funder
National Health and Medical Research Council
Funding Amount
$445,270.00
Summary
The ultimate fate of most of our cells is 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 . Inappropriate apoptosis can contribute to cell loss following heart attacks, stroke or neurodegenerative diseases, such as Alzheimer s or Parkinson s disease. Conversely, when cell death fails to occur, abnormal cells can accumulate and lead to cancer. In addition, because drugs ....The ultimate fate of most of our cells is 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 . Inappropriate apoptosis can contribute to cell loss following heart attacks, stroke or neurodegenerative diseases, such as Alzheimer s or Parkinson s disease. Conversely, when cell death fails to occur, abnormal cells can accumulate and lead to cancer. In addition, because drugs that are used to treat cancer may exert their effect by inducing apoptosis, a failure of this suicide response may cause resistance to chemotherapy. The genes of the apoptosis pathway function either to promote or inhibit cell death. We have found that 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. If these genes are mutated then apoptosis does not occur and a functional cell may survive. The distinction between cells that decide fate and those that do not is crucial because it is only the genes that decide cell fate that can act as cancer genes, and are valid targets for therapy. We use a model in which apoptosis is caused by removal of a growth factor, using cell lines derived from mice that lack particular genes in the cell death pathway. These cells proliferate normally in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn. Because these cells are sensitive to chemotherapeutic drugs, we can also determine the contribution these genes make to cancer drug sensitivity. Using this system, we have discovered that Puma, a gene known to be required for apoptosis in response to radiation, is also a critical activator of apoptosis following growth factor withdrawal. We will determine the manner in which Puma is regulated by growth factors, as well as identify and characterise other key components.Read moreRead less
Investigating The Role Of Mutant P53 And MCL-1 In The Sustained Growth Of MYC Lymphomas And Strategies For Targeted Therapy
Funder
National Health and Medical Research Council
Funding Amount
$616,940.00
Summary
A large number of human cancers have abnormal expression of a protein called MYC, leading to rapid growth. We found that when another protein called MCL-1 was inactivated, the lymphomas regressed. Importantly, mutations in the tumour suppressor gene called p53 are frequently found in cancer cells and we noticed that this could reduce the dependency on MCL-1. We aim to investigate this further in this grant proposal, in part using a novel drug that targets MCL-1.
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.
Learning The Mechanisms Of Programmed Cell Death And Tumour Suppression To Develop Novel Cancer Therapies
Funder
National Health and Medical Research Council
Funding Amount
$863,910.00
Summary
Our bodies prevent the development of cancer through tumour suppressive processes, which also affect the outcome of cancer therapy. Programmed cell death (apoptosis) is one such process, and defects in apoptosis promote cancer development and impair the response of tumour cells to anti-cancer therapies. My laboratory uses molecular biology and cell biology approaches to investigate the mechanisms of cell death and tumour suppression, partnering with pharma to develop novel cancer therapies.
Structural Investigations Of The Bax And Bak Cell Death Apparatus
Funder
National Health and Medical Research Council
Funding Amount
$275,509.00
Summary
Programmed cell death is a process by which the body keeps rogue cells in check. Cancer cells adapt to avoid this process and thus evade this important defence mechanism. This project seeks to understand the machinery that controls programmed cell death at the molecular level. It will provide the atomic details of how this machinery is regulated and how it functions to induce cell death. These insights will provide new avenues for targeting this machinery for a new generation of cancer therapeut ....Programmed cell death is a process by which the body keeps rogue cells in check. Cancer cells adapt to avoid this process and thus evade this important defence mechanism. This project seeks to understand the machinery that controls programmed cell death at the molecular level. It will provide the atomic details of how this machinery is regulated and how it functions to induce cell death. These insights will provide new avenues for targeting this machinery for a new generation of cancer therapeutics.Read moreRead less
The Axis Of Bcl-2, Plasmacytoid DCs And Lupus As A Basis For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$712,172.00
Summary
Systemic lupus erythematosus (SLE) affects 1 in 1000 Australians, mostly women. Here the immune system goes awry and makes antibodies against the body’s own components including the body’s DNA. This leads to damage to many parts of the body including kidneys, joints, brain and heart. It is incurable. A particular immune cell controls the development of this disease and we have found this cell is selectively killed by an inexpensive drug, which we hope will be a better way of treating SLE.