Mitogenic And Metabolic Signalling Via The Insulin Recptor Isoform-A
Funder
National Health and Medical Research Council
Funding Amount
$533,541.00
Summary
A novel mechanism of stimulating cancer cell survival and growth has been identified which involves insulin and insulin-like growth factor-II acting via the insulin receptor isoform A. This proposal will identify the mechanisms by which these ligands stimulate growth rather than metabolism via the insulin receptor-A. This information will be used in future design of novel molecules to inhibit cancer growth without interfering with insulin's normal metabolic functions.
The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via ....The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via an alternative form of the insulin receptor. We will join with our international collaborator to bring together a team of biochemists and protein structural biologists who are world leaders in understanding protein interactions in the insulin and insulin-like growth factor systems. As relatively little is known about this alternate pathway we propose to define the mechanism of binding of insulin-like growth factor-II to the alternate insulin receptor isoform. Using a combination of well-established and novel techniques we will map the interaction. This knowledge will allow design of specific inhibitors to block the action of insulin-like growth factor-II in promotion of cancer cell growth and survival without disruption of the metabolic actions of the insulin receptor.Read moreRead less
Endocrine And Autocrine Regulation Of Breast Cancer Cell Growth By IGF Binding Protein-3 (IGFBP-3).
Funder
National Health and Medical Research Council
Funding Amount
$497,250.00
Summary
The insulin-like growth factor (IGF) system of growth factors and their regulatory proteins is essential for normal growth, but is also involved in a number of overgrowth disorders. Some clinical studies have shown that a high level of IGF-I in the blood increases the risk of breast cancer in some women, but if the protein which carries it in the circulation, IGFBP-3, is also high, the risk is reduced. It has therefore been suggested that IGFBP-3 may be useful in the treatment of breast cancer. ....The insulin-like growth factor (IGF) system of growth factors and their regulatory proteins is essential for normal growth, but is also involved in a number of overgrowth disorders. Some clinical studies have shown that a high level of IGF-I in the blood increases the risk of breast cancer in some women, but if the protein which carries it in the circulation, IGFBP-3, is also high, the risk is reduced. It has therefore been suggested that IGFBP-3 may be useful in the treatment of breast cancer. This is supported by laboratory studies showing that IGFBP-3 can inhibit cell division and stimulate cell death in many cell types, including breast cells. However, some cells are resistant to IGFBP-3 s inhibitory effects, and in some cases IGFBP-3 may stimulate cells to grow and divide. In fact, the amount of IGFBP-3 present in breast tumours is highest in the fastest growing, most malignant tumours, suggesting that IGFBP-3 may be stimulating their growth. Our laboratory data indicates that breast cancer cells which produce a high level of IGFBP-3 grow faster as tumours than cells which produce little or no IGFBP-3. We believe that this is because IGFBP-3 interacts with another hormone system which is involved in rapid tissue growth, the EGF system, and increases its ability to stimulate breast cells to divide. These observations raise a number of important questions: how does IGFBP-3 interact with the EGF system to stimulate tumour growth; does IGFBP-3 from the blood promote the growth of EGF-sensitive tumours; and can the interaction between IGFBP-3 and the EGF system be abolished, or switched from growth stimulatory to growth inhibitory, thus inhibiting tumour growth. Answering these questions will provide important new information regarding IGFBP-3 s stimulatory and inhibitory actions, and the role of endocrine IGFBP-3 in tumour growth, and have the potential to lead to the development of novel therapies involving IGFBP-3 for the treatment of overgrowth disorders.Read moreRead less
Structural And Functional Investigation Into The Cooperation Of IGF And Vitronectin-binding Receptors In Cell Migration
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
Summary
Breast cancer is the most commonly diagnosed form of cancer in Australian women, accounting for 26% of diagnosed cancers and 21% of cancer deaths among women. One in fourteen Australian and one in nine women worldwide will develop breast cancer in their lifetime. Significantly, approximately one in four of those diagnosed will die from their disease. The primary factor that determines survival is early diagnosis and treatment. Indeed, the primary tumour itself rarely causes death. Rather, the di ....Breast cancer is the most commonly diagnosed form of cancer in Australian women, accounting for 26% of diagnosed cancers and 21% of cancer deaths among women. One in fourteen Australian and one in nine women worldwide will develop breast cancer in their lifetime. Significantly, approximately one in four of those diagnosed will die from their disease. The primary factor that determines survival is early diagnosis and treatment. Indeed, the primary tumour itself rarely causes death. Rather, the dissemination of tumour cells to remote sites and the establishment of secondary tumours in critical sites in the body is the major mechanism of mortality. An understanding of the processes that lead to the establishment of secondary tumour bodies and strategies to halt the spread of cancer beyond the primary site are therefore highly valuable. Two factors thought to be pivotal in breast cancer metastasis are altered interactions with the microenvironment surrounding cells and exposure to increased levels of hormones and growth factors, such as the insulin-like growth factors (IGFs). We have recently found that IGFs form complexes with a protein called vitronectin, found in the microenvironment, and these complexes can stimulate increased migration of breast cancer cells. This project will examine the interaction of IGF and VN in stimulating cell migration and in particular, aims to identify the genes involved in the enhanced cell migration. In addition we will examine how the IGF:vitronectin complexes form and how these in turn interact with receptors on the surface of the cell. The data obtained will provide critical fundamental information that is necessary to develop targeted therapies for the treatment and control of breast cancer.Read moreRead less
High-affinity Protease-resistant Analog Of Insulin-like Growth Factor Binding Protein-2: Potential Cancer Co-Therapeutic
Funder
National Health and Medical Research Council
Funding Amount
$294,423.00
Summary
In many human cancers, including prostate and breast cancer, serum levels of insulin-like growth factor (IGF)-II are elevated, and this growth factor has been strongly implicated in promoting the progression of these tumours. The action of IGF-II in stimulating tumour growth is mediated through Type 1 IGF receptors on the surface of the cells. The IGF binding protein, IGFBP-2, has been shown to increase the action of IGF-II in some cancer cells in vitro. by binding to the outside of the cells as ....In many human cancers, including prostate and breast cancer, serum levels of insulin-like growth factor (IGF)-II are elevated, and this growth factor has been strongly implicated in promoting the progression of these tumours. The action of IGF-II in stimulating tumour growth is mediated through Type 1 IGF receptors on the surface of the cells. The IGF binding protein, IGFBP-2, has been shown to increase the action of IGF-II in some cancer cells in vitro. by binding to the outside of the cells as an IGF-II-IGFBP-2 complex and then presenting the IGF-II to the receptor by a process of sustained release. We propose to produce a very high affinity form of insulin-like growth factor binding protein-2 (OOptimised IGFBP-2O) which will sequester the IGF-II and effectively prevent it from binding to the receptor or the native IGFBP-2. We shall also engineer the OOptimised IGFBP-2O so that it is unable to bind to the outside of the cells. With this novel peptide, OOptimised IGFBP-2O, we will test the hypothesis that the growth of insulin-like growth factor (IGF)-dependent tumours can be arrested by preventing the localisation and presentation of IGF-II to IGF receptors. We expect that the availability of such a sequestering agent for IGF-II will increase the effectiveness of current cancer chemotherapy agents since it is known that IGF-II can help save cancer cells from chemotherapy-induced death.Read moreRead less