Phosphatidylinositol 3-kinase Mutations Associated With Ovarian, Colon And Breast Tumours
Funder
National Health and Medical Research Council
Funding Amount
$154,000.00
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. Recent functional and genetic studies in a number of different tumour types (including colon and ovarian) have suggested that members of the phosphatidylinositol 3-kinase (PI3K) enzyme family may be oncogenes (cancer-causing genes). However, strong evidence confirming a causal role for PI3K in human cancer is yet to be reported. Our research proposal outlines a study to address this issue. We have preliminary data demonstrating mutations in at least one member of this enzyme family in a number of tumours. We now propose to undertake a comprehensive analysis of the spectrum, and frequency, of PI3K mutations that occur in colon, breast and ovarian tumours. These studies will allow us to make a definitive assessment of the role of PI3K in the development human cancer. In addition to furthering our understanding of the processes involved in the initiation and progression of human tumours, this project also has the potential to identify new markers for the early detection of cancer and novel targets for new anti-cancer therapies.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
Understanding The Role Of PI 3-kinase Mutations In Gastrointestinal Tumourigenesis
Funder
National Health and Medical Research Council
Funding Amount
$283,880.00
Summary
Mutations in the PIK3CA gene are frequently found in bowel cancers but it remains unclear exactly how these mutations are involved in cancer development. We will exploit a unique mouse model to explore the role of PIK3CA mutations in the initiation, progression and-or metastasis of gastrointestinal cancers. This work will provide critical new insights into the biology of PIK3CA mutations and lead to the development of better models for the testing of new anti-cancer therapies.
Studies On The Tumour-associated PIK3CA(H1047R) Mutation Using In Vitro And In Vivo Models Of Breast And Ovarian Cancer
Funder
National Health and Medical Research Council
Funding Amount
$583,312.00
Summary
PIK3CA mutations are frequently found in breast and ovarian cancers but how they cause cancer is not clear. We will exploit a unique mouse model to investigate the functional effects of PIK3CA mutations in cells and their role in cancer development. Understanding the mechanisms by which PIK3CA mutations regulate cell function and drive tumour growth will allow the rationale design of novel anti-cancer agents that specifically target this important cancer pathway.
Studies On The Role Of The P101 Component Of The Class 1B PI 3-Kinase In Cell Migration And Activation.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
This research will determine the biological role of a protein of unknown function that is likely to participate in movement of white blood cells through the body. The outcome of this research will increase our basic knowledge of how the immune system functions and could lead to alternate therapeutic strategies for the control of autoimmune diseases.
Regulation Of 14-3-3 Monomerisation Controls Cell Life/death Fate
Funder
National Health and Medical Research Council
Funding Amount
$524,770.00
Summary
14-3-3 proteins are becoming increasingly recognised as major multifunctional proteins that control key aspects of normal and pathological processes. Although initially viewed as inert components of signalling, we have now recognised for the first time that these are very dynamic proteins that can be regulated. Our main aim is to understand the regulatory mechanisms controlling the different dynamic forms of 14-3-3 and how each form in turn controls the process of life and death.
Regulation Of PtdIns(3,4)P2 Signalling By Inositol Polyphosphate 4-phosphatase-1
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. 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. We have idenitified a novel enzyme called the inositol polyphosphate 4-phosphatase that appears to regulate cell proliferation and differentiation.
Characterization Of A Novel Regulator Of Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$592,235.00
Summary
PI3K is an enzyme required for new blood vessel formation during embryo development as well as in response to tumour formation. We have identified a novel enzyme that opposes PI3K signals and we hypothesise that it regulates new blood vessel formation in various physiological settings. We propose to investigate the role of this enzyme in blood vessels using mouse models in which this protein is reduced or absent.
Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insu ....Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insulin are diminished and cells become increasingly unable to uptake glucose. Recent studies have demonstrated that a novel enzyme known as SHIP-2 may play a role in regulating insulin action in cells. Deletion of SHIP-2 in mice results in these animals have increased sensitivity to insulin, low blood glucose levels, and a greatly enhanced ability to take up glucose in cells in response to low dose insulin. Our laboratory has been working on the cellular mechanisms regulating SHIP-2 function. We have recently revealed the intracellular location of SHIP-2 and also demonstrated how SHIP-2 is localized in the cell. These studies have shown that SHIP-2, via interactions with other proteins, regulates the actin cytoskeleton immediately beneath the cell membrane and this may be a mechanism for facilitating cellular glucose uptake. This research proposal aims to determine how SHIP-2 facilitates glucose uptake into cells. We will make cell lines and transgenic animals which express high levels of this enzyme and determine the functional consequences on insulin stimulated glucose uptake. Collectively these studies in the long term may facilitate better treatment strategies for diabetic patients.Read moreRead less
Identification And Characterization Of Novel PI3-kinase Signal Transducing Elements In Platelets
Funder
National Health and Medical Research Council
Funding Amount
$457,500.00
Summary
Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury. Activation and regulation of these processes relies on a complex network of signal transduction processes, involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in regulating platelet responses is the enzyme phosphatidylinositol 3-ki ....Platelets play an important role in blood clotting and blood vessel repair. Upon vessel injury, platelets rapidly adhere to the site of damage where they undergo dramatic shape change to spread over the site of injury. Activation and regulation of these processes relies on a complex network of signal transduction processes, involving the integration of multiple receptors and pathways. One pathway demonstrated to play a role in regulating platelet responses is the enzyme phosphatidylinositol 3-kinase (PI3-kinase) and its lipid products PtdIns(3,4,5)P3 and PtdIns(3,4)P2. However, very little is known about exactly how PI3-kinase and its products regulate the platelet responses. Our research studies aim to gain a deeper understanding into the molecular mechanisms of PI3-kinase signal transduction in platelets, through the identification and characterization of novel platelet proteins that bind to PI3-kinase lipid products, and to define what role these proteins play in platelet PI3-kinase dependent responses.Read moreRead less