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
Novel Endocrine Approaches To Diagnosis & Treatment Of Men With Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$926,980.00
Summary
Most men are diagnosed with localised prostate cancer, others have advanced disease. Vision: Identify how tumours are insignificant vs aggressive (Aim 1.1 & 1.2). Predict which tumours will progress to incurable disease (Aim 1.3) and how to target them (Aim 1.4). Discover how each patient tumour is different (Aim 2.1) and pre-clinically test new therapies (Aim 2.2). Outcomes: practice changing discoveries that identify novel therapeutic targets & biomarkers improving diagnosis and treatment.
Selective Activation Of Androgen Receptor To Treat Estrogen Receptor Positive Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$843,325.00
Summary
A major challenge in breast cancer research is to find alternative drugs to treat women with drug-resistant disease. What’s new and exciting is a novel type of drug that mimics the ability of natural androgen hormones to inhibit estrogen action in breast cancers without undesirable masculinising side effects. This research will greatly facilitate the introduction of a new breast cancer treatment into clinics worldwide by the development of a new test that can predict response to this treatment.
The Regulation Of Aromatase In The Context Of Obesity And Postmenopausal Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$436,601.00
Summary
Current hormone therapy for breast cancer using inhibitors of oestrogen formation results in serious side-effects including bone loss, joint pain and possibly cognitive issues. Our current work is aimed at understanding how oestrogen formation is regulated with the goal of developing breast-specific inhibitors of oestrogen formation to obviate these problems. In addition, this work is aimed at devising therapeutic intervention to break the linkage between obesity and breast cancer.
Modulation Of Cytoskeletal Structure By Progesterone Receptor Isoforms
Funder
National Health and Medical Research Council
Funding Amount
$337,650.00
Summary
Ovarian hormones are fundamental regulators of normal cell growth and differentiation, and crucial to the development and progression of breast cancer. We have recently shown that the ovarian hormone progesterone can influence the expression of proteins in the cell scaffolding, known as the cytoskeleton. The cytoskeleton is responsible for maintaining cell shape, and there is growing evidence that alterations in the cytoskeleton can actually cause normal cells to become cancerous. We have shown ....Ovarian hormones are fundamental regulators of normal cell growth and differentiation, and crucial to the development and progression of breast cancer. We have recently shown that the ovarian hormone progesterone can influence the expression of proteins in the cell scaffolding, known as the cytoskeleton. The cytoskeleton is responsible for maintaining cell shape, and there is growing evidence that alterations in the cytoskeleton can actually cause normal cells to become cancerous. We have shown that progesterone affects the levels of a cytoskeletal protein called tropomyosin, which plays a pivotal role in cell shape maintenance. We have hypothesised that this effect may be important in the cell shape changes in breast cancer that lead to metastasis. In this grant, we will investigate the role of the progesterone receptor in controlling the expression of the cytokeleton; we will investigate whether cell shape changes caused by progesterone cause more aggressive behaviour in breast cancer cells and we will determine whether there are changes in cytokeletal proteins in breast tumours. This will provide a rational basis for further studies aimed at delineating the significance of hormonal regulation of cell architecture.Read moreRead less
Research Fellowship – Genetic Epidemiology Studies Of Hormonal Cancers To Inform Improved Healthcare
Funder
National Health and Medical Research Council
Funding Amount
$772,209.00
Summary
This study aims to identify genetic factors that influence the development of endometrial and other cancers, and to develop statistical and laboratory methods that can better determine if variation in a known cancer gene is disease-causing. The results will be used to identify and prioritise individuals at greatest risk of cancer for the most appropriate clinical management. Discovery of novel cancer genes will improve our understanding of disease development to develop future therapies.
Hormonal Influences In The Pathogenesis Of Ovarian Tumours
Funder
National Health and Medical Research Council
Funding Amount
$264,601.00
Summary
Ovarian cancer is one of the most common malignancies affecting the female reproductive system. We have found that two types of tumour of the ovary produce a hormone called inhibin; these tumours are also known to produce the steroid hormone estrogen. In these studies we are seeking to determine the genetic changes in the tumours that cause the production of these hormones. We suspect that these genetic changes are also the same changes which contribute to the development of the cancers. In orde ....Ovarian cancer is one of the most common malignancies affecting the female reproductive system. We have found that two types of tumour of the ovary produce a hormone called inhibin; these tumours are also known to produce the steroid hormone estrogen. In these studies we are seeking to determine the genetic changes in the tumours that cause the production of these hormones. We suspect that these genetic changes are also the same changes which contribute to the development of the cancers. In order to identify these genes we will draw on our knowledge of the genes that are important in the controlof growth and hormone secretion in normal ovarian cells. To assist this molecular analysis we will use two ovarian cell lines in culture that have many of the features of the primary tumours including inhibin secretion. We will also use new techniques to scan over 500 genes involved in tumours in general to see whether we detect any unusual or distinctive patterns in this sub-group of tumours. A genome wide scanning technique will be used to seek changes in the DNA of the tumours, inparticular loss of genetic material or amplification of regions. Identification of the genetic changes within these tumours should enable better systems of classification, enhance prognostication and provide specific targets for the development of appropriate treatment strategies.Read moreRead less
Extension Of A Two-stage Genome-wide Association Study Of Endometrial Cancer: Validation Of Endometrial Cancer Risk-associated Alleles And Identification Of ‘multiple-cancer’ Risk Loci
Funder
National Health and Medical Research Council
Funding Amount
$703,870.00
Summary
Endometrial cancer (uterine/womb cancer) is the most common invasive gynaecological cancer in Australia. Each year more than 1400 women are affected by the condition. Our study is comparing genetic markers seen in patients to unaffected controls in an unbiased way to identify genetic factors that increase risk of this and other hormonal cancers, to better understand the causes of cancer. This will provide information for to help develop targeted therapies to prevent progression in the future.
Impact Of Progesterone Receptor Subnuclear Localisation On Progesterone Action In Endocrine Target Cells
Funder
National Health and Medical Research Council
Funding Amount
$459,514.00
Summary
Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We ....Breast cancer affects 10,000 Australian women annually and is a major cause of cancer death. The hormone progesterone, which is produced by the ovaries in women, is responsible for some aspects of the development of the normal breast in women and is also implicated in the development and response of breast and endometrial cancers. In normal cells progesterone acts via a specific protein (or receptor) in the nucleus, and we have shown that this protein accumulates into foci when it is active. We have noticed that in cancers, this accumulation is disrupted, and this is a bad sign for the cancer. As breast cancer develops, it causes many dramatic changes in the structure of cells of the breast, and particularly in the nucleus, which carries the genetic information that programs cancer cell behaviour. The nucleus normally is highly organised into compartments, which carry out different functions of the cell, such as duplication of the DNA, repair of DNA after damage, and switching on and off of particular genes important to the function of the cell. This organisation is altered dramatically in cancer cells, and it seems that this altered organisation is responsible for altered function. In this project we aim to work out what makes the receptor for progesterone form foci, how these foci are involved in the action of progesterone, and how the changed structure of the nucleus changes this process. This project will link the structure of the cell nucleus with the ability of progesterone to switch on or off particular genes, and this will provide the first signposts of how changes seen in cancer cell nuclei are reflected in changed hormonal signalling. Healthy women are regularly exposed to progestins in oral contraceptives and hormone replacement therapy. The known increased risk of breast cancer as a result of exposure to progestins creates an imperative to understand how progesterone may have aberrant effects. This project will address this important health issue.Read moreRead less