Signalling Networks As Targets For Antibody Therapy In Glioma.
Funder
National Health and Medical Research Council
Funding Amount
$526,683.00
Summary
Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. It is also possible to generate antibodies that bind to receptors on the surface of can ....Antibodies are a major component of the bodies immune system that bind (i.e. stick) to foreign substances such as viruses. Once bound, these antibodies can activate other parts of the immune system, which help destroy the foreign substance. Analogous to the situation above, a number of institutions are testing antibodies that bind to cancer cells, in order to determine if they are able to destroy these cells. It is also possible to generate antibodies that bind to receptors on the surface of cancer cells and block their function. If you target a receptor critical to the growth or survival of a cancer cell in this way, then swtiching-off this signal may inhibit tumor growth. In this proposal we plan to test a panel antibodies that recognize receptors important to the growth of brain cancer. Two of these antibodies have been generated and the other two will be made as part of this proposal. A key aspect of this proposal will be testing these antibodies in combination to determine how many receptors need to be targeted in order to get complete tumor regressions in animal models. Overall this work will help us identify new therapeutic strategies for the treatment of brain cancer. Finally, we will also analyze the way different receptors interact together in brain cancer cells.Read moreRead less
Biological And Clinical Characterisation Of Human Phosphatidylinositide 3-kinase Mutations
Funder
National Health and Medical Research Council
Funding Amount
$553,776.00
Summary
Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact ....Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact on our society. Unfortunately, though, we still do not understand the basic molecular and-or biochemical abnormalities that initiate and-or drive the development of these cancers. Our laboratory has recently reported a high frequency of mutation of the phosphoinositide 3-kinase (PI3K) gene PIK3CA in breast, colorectal and ovarian tumours. This work, funded by the NHMRC, has not only confirmed that PI3K is a bone fide human oncogene but also that mutations in the PI3K family of genes are one of the most common, and thus potentially one of the most important, genetic abnormalities in solid human tumours. In the current proposal, we aim to extend and complement our genetic studies by addressing the biological consequences and clinical significance of the mutations we have identified. This will provide crucial new insights into the biology of human tumourigenesis and further our understanding of the critical pathways and processes involved in the initiation and progression of human tumours. Such knowledge will help us to identify novel markers for diagnosis, prognosis and the early detection of cancer and enable a rational approach to the design of new anti-cancer therapies.Read moreRead less
Molecular Identification Of Causative Genetic And Epigenetic Alterations That Induce And Promote Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$381,821.00
Summary
The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that under ....The majority of mouse models currently employed to study colorectal cancer have two failings. The first is that they tend to focus on small intestinal cancers rather than colorectal cancers. It is important to note that small intestinal cancers are in the minority of gastrointestinal cancers in humans. The second problem is that the genetic lesions introduced into mice are mostly in all cells throughout development. This is a poor representation of the random nature of genetic changes that underpin the probable cause of colon cancer. We therefore propose to genetically engineer unique mouse models that focus on colon cancer to most closely replicate the situation in human disease. These models will then be available to others and us to develop and test therapies to prevent and-or treat colorectal cancer that will ultimately be used in patients.Read moreRead less
Tumour Suppressor Networks: The Role Of SHIP-1 And Lyn In Suppressing Haematopoietic Tumours
Funder
National Health and Medical Research Council
Funding Amount
$469,526.00
Summary
Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in ....Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in some instances Lyn and SHIP-1 participate in the same biochemical pathway. We have created mice that are unable to make Lyn protein, and have found that these mice develop blood cell tumours. Mice lacking SHIP-1 develop a number of haematological defects, but die at a young age due to an inflammatory lung condition, making an assessment of the role of SHIP-1 in age-dependent tumour development difficult. We now wish to study the role of SHIP-1 in tumour development, by generating mice that lack SHIP-1 in specific white blood cell compartments. We are also investigating how SHIP-1 and Lyn cooperate in tumour suppression, and we have recently generated mice that simultaneously lack both SHIP-1 and Lyn. Preliminary studies indicate that compound mutant mice develop multiple haematological malignancies. We will fully characterize tumour development in these animals, and determine the molecular basis for this pathology. We will focus on two pathways that have been previously implicated in oncogenesis. These studies will improve our insight into how Lyn and SHIP-1 cooperate in blood cell development, cellular homeostasis and oncogenesis, and add to our biological and biochemical understanding of tumour suppressor networks.Read moreRead less
The Role Of PIPP In Cell Polarization And Proliferation.
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon stimulation, a series of signals are generated inside the cell which lead to cell division and development. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. Following growth factor stimulation, P ....Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon stimulation, a series of signals are generated inside the cell which lead to cell division and development. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. Following growth factor stimulation, PI3-kinase generates a molecule known as PtdIns(3,4,5)P3 which leads to the activation of many proteins in the signaling pathway. All cells which have PI3-kinase also have enzymes which act to switch off the signals generated by PI3-kinase and thus may play a role in preventing cancer and regulating cell development. We have identified a new enzyme known as PIPP and have shown that it acts to switch off the signals generated by PI3-kinase. We plan to investigate the role of PIPP by increasing or decreasing the amount of PIPP in cells and analysing the effects on cell growth and development. We have also identified a number of proteins which bind to PIPP and we will investigate the role these proteins play in regulating cell signaling. In addition, we plan to characterize the function of PIPP in a whole animal by generating mice which lack PIPP (knockout mice) and assessing the effects on development and cancer.Read moreRead less
Role Of SOCS3 In Mammary Gland Development And Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$224,278.00
Summary
We are studying the role of a family of inhibitory molecules (SOCS) in breast tissue; these proteins have been established to have critical roles in the immune system and in regulating growth of the entire animal. We have demonstrated that one member of this family can block the action of the prolactin hormone and have recently obtained evidence that another member of this family, SOCS3, affects survival of breast cells. Furthermore, this protein leads to increased growth when overexpressed in b ....We are studying the role of a family of inhibitory molecules (SOCS) in breast tissue; these proteins have been established to have critical roles in the immune system and in regulating growth of the entire animal. We have demonstrated that one member of this family can block the action of the prolactin hormone and have recently obtained evidence that another member of this family, SOCS3, affects survival of breast cells. Furthermore, this protein leads to increased growth when overexpressed in breast cells. We propose to define the normal role of this gene in mouse mammary tissue and to examine the consequences of expressing the gene at high levels in the mammary glands of mice. Inappropriate expression of this gene may predispose humans to breast cancer. SOCS3 expression will be directly studied in a cohort of primary invasive breast cancers with associated clinical outcome data, to determine whether it has a role as a potential prognostic marker.Read moreRead less
APC Mutation And The Initiation Of Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$606,267.00
Summary
Colorectal (or bowel) cancer is a major health problem in Australia. At present it is the most common cancer, approximately 1 in 21 Australians will develop the disease in his-her lifetime. The risk of bowel cancer increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for advanced colorectal cancer are not very effective. Mortality from colorectal cancer is high, being second only to lung cancer as the leading cause of cancer death in Australia. ....Colorectal (or bowel) cancer is a major health problem in Australia. At present it is the most common cancer, approximately 1 in 21 Australians will develop the disease in his-her lifetime. The risk of bowel cancer increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for advanced colorectal cancer are not very effective. Mortality from colorectal cancer is high, being second only to lung cancer as the leading cause of cancer death in Australia. The development of colorectal cancer is affected by both genetic and environmental factors. Colorectal cancer progresses through a number of distinct pathological stages. This is thought to be the result of the progressive aquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations in a gene known as APC are associated with the very early stages of tumour formation in at least 80% of colorectal tumours. Our research is aimed at understanding how alterations in APC influence the behaviour and growth of colonic cells. We have developed a novel system where normal mouse colon can be maintained and grown for up to 2 weeks in a Petri dish. Alterations in the APC gene and other colon cancer genes will be introduced into the normal epithelial cell lining and the effects on the growth and behaviour of the cells in organ culture will be analysed. Our hypothesis is that changes in the APC gene affects the way cells migrate, divide and move. This work should improve our knowledge of the cellular changes that occur during tumour initiation in the bowel and aims to contribute to the design of new therapies for early intervention in colon cancer.Read moreRead less