Molecular Characterisation Of Clathrin-independent Endocytosis In Migrating Cells
Funder
National Health and Medical Research Council
Funding Amount
$870,495.00
Summary
Cell migration is an essential feature of physiological processes involved in embryo development, as well as disease conditions such as cancer metastasis. Cell movement requires extensive changes to the cell surface. We have identified a vital pathway involved in membrane trafficking during cell migration. This proposal aims to identify the cellular components involved in this pathway, screen for new inhibitors, and characterise the role of this pathway in migrating cancer cells.
Mechanisms Of CD44v2-10-mediated Tumour Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to investigate the mechanisms by which specificdomains in the CD44 variants actually cause tumour spread. Understanding of the various mechanisms involved in tumour spread, and targeting the functions of the domains has enormous potential as a therapeutic target.Read moreRead less
CD44v3 And V6 As Targets For Anti-metastasis Therapy
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, includi ....Cancer metastasis remains the principal cause of treatment failure in malignant disease. Current therapies for metastases are generally non-specific, and can cause considerable systemic toxicity. The ideal target for metastasis therapy would be expressed by a broad range of tumours, but be restricted in expression in normal tissues. CD44 is a family of widely expressed cell-surface adhesion molecules and its members are implicated in a variety of physiological and pathological processes, including tumour progression and metastasis. CD44 has considerable molecular diversity and its broad range of known biological activities suggests that multiple domains in the molecule may confer different biological functions. The core CD44 molecule, termed CD44s, is the most commonly expressed CD44 molecule. CD44 variants (termed CD44v) are much more restricted in their expression in normal tissues, and hence may make specific targets for anti-metastasis therapy. We have shown that CD44 variants are expressed by colorectal tumours from the earliest stages of tumour development, and that theses variants are found to be expressed by colorectal hepatic metastases. We targeted two key domains in the variants and found that by inhibiting expression in these domains we showed complete abrogation of metastasis, and of primary tumour growth in mice. Hence these domains in the CD44 molecule are directly involved in cancer spread. We propose to develop a number of specific methods of targeting CD44 in order to prevent the spread of cancer. We have and will develop additional agents directed to these key domains in CD44. Targeting these domains has great potential as metastasis therapy.Read moreRead less
Functional Evaluation Of BRCA1 & BRCA2 Unclassified Sequence Variants And Identification Of Critical Pathogenic Domains.
Funder
National Health and Medical Research Council
Funding Amount
$331,312.00
Summary
The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the se ....The major genes that predispose to hereditary breast cancer are called BRCA1 and BRCA2. Most mutations in these genes cause the protein product to be truncated and inactive. However there are many families in which such truncating mutations are not found, but instead there are sequence changes that slightly alter the protein product. It is often difficult to predict whether these sequence variants are likely to cause hereditary breast cancer simply by looking at the position and nature of the sequence change. Consequently, it is not possible to offer informative genetic counselling to these women or their at-risk family members. Assessment of the potential pathogenicity and functional significance of these unclassified sequence variants will be directly useful with regard to the clinical management of these women and their families, and will develop our current understanding of how different domains of these genes contribute to their role as cancer susceptibility genes.Read moreRead less