Inhibition Of Estrogen Signalling By Androgen Receptors: A Potential Mechanism For Suppression Of Breast Cancer Growth.
Funder
National Health and Medical Research Council
Funding Amount
$525,000.00
Summary
Breast cancer is a major health problem in Western countries including Australia, where it is the second-leading cause of cancer deaths in women. Breast cells require female sex hormones, called estrogens, for their growth and survival and consequently most current treatments for breast cancer aim to block the actions of these hormones in breast cancer cells. However there is still a large proportion of women who do not respond to these therapies or have an initial response but subsequently deve ....Breast cancer is a major health problem in Western countries including Australia, where it is the second-leading cause of cancer deaths in women. Breast cells require female sex hormones, called estrogens, for their growth and survival and consequently most current treatments for breast cancer aim to block the actions of these hormones in breast cancer cells. However there is still a large proportion of women who do not respond to these therapies or have an initial response but subsequently develop resistance. Evidence from our laboratory and others indicates that the male sex hormones, androgens, also play an important role in breast cancer. Androgens oppose the effects of estrogens in breast cancer cells, and inhibit their growth. Historically androgens were used to treat patients with advanced breast cancer, with good results, but the masculinising side effects (eg excess hair growth and acne) of these hormones led to a discontinuation of their use since the 1960s. The major objective of our current studies is to determine how androgens can stop breast cancer cells from growing by investigating the effects of the androgen receptor, which mediates the growth regulatory effects of androgens, in breast cancer cells. We believe that a better understanding of this signalling pathway could potentially lead to new treatments for breast cancer that act more specifically to inhibit cancer growth without the unpleasant side effects of androgenic drugs.Read moreRead less
Geldanamycin Derivatives: Novel Inhibitors Of Androgen Signalling For The Treatment Of Metastatic Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$316,320.00
Summary
Prostate cancer is a major health problem in Western Countries including Australia, where it is the most common newly diagnosed invasive cancer and the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis of prostate cancer, many men are still diagnosed with disease that already has or will spread to other sites such as lymph nodes and bone (ie metastatic disease). For those men with metastatic disease, reduction in testicular androgens by surgical ....Prostate cancer is a major health problem in Western Countries including Australia, where it is the most common newly diagnosed invasive cancer and the second leading cause of cancer deaths in men. Although there have been improvements in the diagnosis of prostate cancer, many men are still diagnosed with disease that already has or will spread to other sites such as lymph nodes and bone (ie metastatic disease). For those men with metastatic disease, reduction in testicular androgens by surgical or medical means (ie androgen ablation) is the only effective treatment option available. However, androgen ablation is only palliative, and treatment failure is common, with less than 20% of patients surviving more than 5 years. Recent evidence suggests that the androgen receptor, which mediates the growth regulatory effects of androgens, such as testosterone, is often defective in prostate tumour cells. These altered or mutant receptors may be inappropriately activated and stimulate tumour growth which may explain why treatment fails in a subset of men with advanced prostate cancer. The major objective of our current proposal is to evaluate a novel approach for the treatment of prostate cancer which, based upon our preliminary results, has the potential to be effective even if alterations are present in the androgen receptor. Specifically, we will examine the effectiveness of derivatives of a natural product, the antibiotic geldanamycin, to inhibit prostate tumour growth. The current studies therefore have the potential to result in improved treatment approaches for advanced prostate cancer.Read moreRead less
Colorectal Cancer - Molecular Basis To Targeted Therapeutics.
Funder
National Health and Medical Research Council
Funding Amount
$19,818,386.00
Summary
Cancer of the colon and rectum is the most common form of cancer in Australia. Over 12,000 people are diagnosed each year with colorectal cancer (CRC) and more than one third of people will die of their disease. CRC is caused by mistakes in production of colon cells. Our research aims to discover new ways to detect CRC, develop smart drugs and nanoparticle delivery systems for destroying all types of CRC cells. We will then test our new anti-cancer drugs in clinical trials with CRC patients.
Clinical Trial Of Adjuvant Docetaxel And Doxorubicin For Node Positive Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$185,135.00
Summary
This project is investigating the optimal use of docetaxel and doxorubicin in the treatment of women with breast cancer and involved lymph nodes (N+). Every year 3000 women in Australia, and over 400,000 worldwide are newly diagnosed with N+ breast cancer. Using available treatments more than 60% of these (5 per day in Australia, 4,500 each week worldwide) will die from breast cancer. The efficacy of adjuvant chemotherapy in early breast cancer is well established by the international overview c ....This project is investigating the optimal use of docetaxel and doxorubicin in the treatment of women with breast cancer and involved lymph nodes (N+). Every year 3000 women in Australia, and over 400,000 worldwide are newly diagnosed with N+ breast cancer. Using available treatments more than 60% of these (5 per day in Australia, 4,500 each week worldwide) will die from breast cancer. The efficacy of adjuvant chemotherapy in early breast cancer is well established by the international overview conducted by the Early Breast Cancer Trialist's Collaborative Group (EBCTCG). They have demonstrated the efficacy of adjuvant chemotherapy on reducing mortality and recurrence rates, but current regimens are far from optimal. Docetaxel (Taxotere), a new agent, has effectiveness and manageable side effects in the treatment of advanced breast cancer patients, and can plausibly improve outcomes for patients with early N+ breast cancer by optimal integration into current adjuvant chemotherapy regimens. This clinical trial is designed to compare whether it is advantageous to use docetaxel and-or doxorubicin in combination or sequentially with other currently available chemotherapy drugs.Read moreRead less
The Importance Of VEGF-D, An Angiogenic Protein, For Lymphangiogenesis, Tumor Growth And Metastasis.
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Tumors attract blood vessels to obtain the nutrients for growth. Furthermore, the presence of blood vessels in a tumor enables tumor cells to enter the bloodstream and spread to distant parts of the body - a process known as metastatis that is the major cause of death in cancer patients. The growth of blood vessels - angiogenesis - is the mechanism by which tumors attract the vasculature. The capacity to block tumor angiogenesis would be of great benefit in the clinic as it would restrict both t ....Tumors attract blood vessels to obtain the nutrients for growth. Furthermore, the presence of blood vessels in a tumor enables tumor cells to enter the bloodstream and spread to distant parts of the body - a process known as metastatis that is the major cause of death in cancer patients. The growth of blood vessels - angiogenesis - is the mechanism by which tumors attract the vasculature. The capacity to block tumor angiogenesis would be of great benefit in the clinic as it would restrict both the growth and spread of tumors. Tumor cells attract blood vessels by secreting angiogenic growth factors that stimulate the proliferation of endothelial cells - the cells that form the inner lining of blood vessels. These Vascular Endothelial Growth Factors (VEGFs) are proteins. One VEGF, namely VEGF-D, was discovered in our laboratory at the Melbourne Branch of the Ludwig Institute for Cancer Research. VEGF-D stimulates the growth of blood vessels and possibly lymphatic vessels and is present in the most common human cancers including malignant melanoma and cancer of the breast and lung. We hypothesize that angiogenesis in some tumors is dependent on VEGF-D. Moreover, VEGF-D secreted by tumor cells may stimulate growth of lymphatic vessels - lymphangiogenesis. As metastatic spread often occurs via the lymphatic vessels, tumor lymphangiogenesis induced by VEGF-D may contribute to metastasis. The purpose of the research project is to determine the role of VEGF-D in tumor angiogenesis and lymphangiogenesis. Firstly we will thoroughly characterize the localization of VEGF-D in human cancer. Secondly, we will test VEGF-D for lymphangiogenic activity. Thirdly, the growth and metastatic spread in mice of tumors overexpressing VEGF-D will be analysed. Finally, aspects of VEGF-D biochemistry and gene regulation will be studied to develop strategies for inhibition of VEGF-D action in cancer.Read moreRead less
An understanding of the way cells control their complex internal circuitry is relevant to diseases like cancer and leukemia. The main focus of this project is a cellular regulator we identified several years ago called BORIS. Normally dormant in all cells outside the male reproductive organs, BORIS is reactivated in many cancers. We will study the network of factors perturbed when BORIS becomes inappropriately active in cancer cells. Ultimately this project may lead to new treatments for cancer.
Acute myeloid leukaemia (AML) is a major health problem with only about one third of patients being cured. In addition therapies have changed little over the last 20 years. However there is optimism that with greater knowledge of the biochemical changes in AML that are caused by genetic mutations, more effective treatments will be developed. This project therefore aims to increase understanding of the biochemical interplay between two proteins called c-Cbl and Flt3 that are altered in AML.
The Role Of The EphA1 In The Normal Epithelial Organs And In Epithelial Tumour Progression.
Funder
National Health and Medical Research Council
Funding Amount
$564,500.00
Summary
The Eph family of proteins were initially found to be important in normal development. In humans this corresponds to the first 12 weeks of pregnancy. In parallel with these studies, other work provided evidence of abnormally high levels of these proteins in a number of human cancers. More recent evidence suggests that these proteins have important roles in the maintenance of normal tissues and in non-malignant diseases. This proposal seeks to understand how one of these proteins (EphA1) works in ....The Eph family of proteins were initially found to be important in normal development. In humans this corresponds to the first 12 weeks of pregnancy. In parallel with these studies, other work provided evidence of abnormally high levels of these proteins in a number of human cancers. More recent evidence suggests that these proteins have important roles in the maintenance of normal tissues and in non-malignant diseases. This proposal seeks to understand how one of these proteins (EphA1) works in the cells which form the skin, liver, kidneys, breast and prostate. These cells also form the lining of the mouth, stomach, bowel and lungs. Understanding how the EphA1 protein and other members of this family cooperate to control the development and maintenance of these organs will allow us to determine whether this protein might be involved in congenital defects and diseases in these organs (such as kidney failure, cirrhosis of the liver and skin diseases). A second main aim of this project is to explore further the observation that Eph proteins are abnormally highly expressed in a wide rangre of human cancers. This abnormal expression is directly correlated with the tumours spreading throughout the body. EphA1 is abnormally highly expressed in cancers of the bowel, lung, breast and prostate. These are the commonest cancers in man and some of the most difficult to treat. The work proposed asks how EphA1 contributes to the development and progression of these cancers. These results will have very direct implications for the development of therapies which target the EphA1 protein.Read moreRead less
The Role Of The M6P-IGF-II Receptor In Regulating Cellular Function
Funder
National Health and Medical Research Council
Funding Amount
$276,598.00
Summary
We will investigate if a cell surface protein that suppresses the growth of breast cancer cells is also able to reduce the cancer spreading to other organs. The part of the molecule required for this effect will be identified so that smaller forms of the protein can be tested to inhibit tumour spread. Genes and proteins altered by the presence of this protein in breast cancer cells will be examined to determine how the protein suppresses tumours and to identify novel tumour markers.
MC1R Polymorphisms Associated With Skin Cancer Risk Phenotypes
Funder
National Health and Medical Research Council
Funding Amount
$519,715.00
Summary
Sunsmart campaigns are a unifying element in the lives of many Australians who wish to ensure protection against the damaging effects of UV rays in sunlight. Although it is evident that lighter skin colours are more susceptible to sun damage, the relationship between sun exposure, skin type and melanoma formation is less clear. It is essential to understand the complex interactions that give rise to melanoma and to identify the genes in individuals that are responsible for this increased risk.