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
Molecular Mechanisms And Control Of Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell fr ....Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell from dividing any further, and acts as a very potent barrier to the cell becoming cancerous. Some normal cells are not subject to this inexorable telomere shortening: these are the germ cells in the testis and ovary, that are responsible for passing on genetic material to the next generation. Such cells express an enzyme, telomerase, which is able to synthesise new telomeric DNA to replace that lost during cell division. 85% of human cancers are also able to prevent shortening of their telomeres - and thus have breached the barrier that normally prevents unlimited cell proliferation - via telomerase activity. Therefore, if drugs that inhibit telomerase can be developed they may be a very useful new form of cancer treatment. We have found, however, that some cancers are able to prevent telomere shortening by a process that does not involve telomerase, and which we refer to as Alternative Lengthening of Telomeres (ALT). One practical implication of this finding for the design of new cancer treatments is that telomerase inhibitors will need to be used in combination with ALT inhibitors. In this study, we will determine A. how normal cells keep the ALT mechanism permanently shut down and B. the molecular details of the ALT mechanism itself. An understanding of these processes may ultimately contribute to the development of novel cancer treatments that disrupt the ability of cancer cells to divide an unlimited number of times.Read moreRead less
The Role Of IQGAP1 In Human High-Grade Glioma And Its Regulation By MiR-124-A
Funder
National Health and Medical Research Council
Funding Amount
$69,137.00
Summary
Survival rates for many cancers are improving, however, for most patients diagnosed with a high grade glioma (HGG) there is limited long term survival. The treatments administered have limited effectiveness due to extensive infiltration of the tumour cells. New therapeutic strategies targeting the invading cell population to further reduce tumour spread are needed. Hence, a better understanding of the mechanisms promoting glioma migration and invasion are urgently required in this fatal disease.
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
TRF2 Protein And T-loop Replication In Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$398,156.00
Summary
Telomere loss acts as a clock telling cells when to stop proliferating. Cancer cells ignore this clock and grow indefinitely by preventing the normal loss of telomeres. Little is known about one of the methods cancers use to preserve telomeres, called ALT, which is employed by some brain tumours and other cancers. We will determine if the TRF2 protein is involved in controlling ALT. This will lay the basis for future anti-cancer treatments targeted at ALT.