Proteomic Screening For Apoptotic Markers In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
The induction of apoptosis, or programmed cell death, is a key factor in the response of tumours to chemotherapeutic agents and ionising radiation; therefore biological markers that predict the clinical outcome to these therapies are needed. Over the past 2 years, our laboratory has developed techniques of protein analysis to evaluate changes in proteins during apoptosis caused by chemotherapeutic agents. Preliminary protein profiling studies of apoptosis induction in human breast cancer cell li ....The induction of apoptosis, or programmed cell death, is a key factor in the response of tumours to chemotherapeutic agents and ionising radiation; therefore biological markers that predict the clinical outcome to these therapies are needed. Over the past 2 years, our laboratory has developed techniques of protein analysis to evaluate changes in proteins during apoptosis caused by chemotherapeutic agents. Preliminary protein profiling studies of apoptosis induction in human breast cancer cell lines showed time-dependent decreases in two proteins, identified as S100A6 and ubiquitin. Both are known to be important in cell function. In the proposed project we will build on our preliminary findings to provide important new information central to the understanding of cancer cell biology and apoptosis in addition to evaluating the ability of anti-cancer treatments to induce apoptosis. Using a combination of protein analysis technologies, this project has the potential to provide reliable and novel biomarkers which will indicate the efficacy and selectivity of anti-cancer treatments in inducing tumour cell death. The knowledge gained in this project will aid clinical assessment of the response to cancer treatment(s) in patients in the form of specific screening assays, and may result in identification and development of effective new agents for cancer treatment and prevention. Furthermore, the outcomes of this project will increase our understanding of fundamental cancer cell biology and apoptosis.Read moreRead less
Characterisation Of The Anti-apoptotic Function Of P-glycoprotein And Transcriptional Regulation Of The MDR1 Gene.
Funder
National Health and Medical Research Council
Funding Amount
$469,500.00
Summary
The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a protein called P-glycoprotein (P-gp) that extrudes cytotoxic drugs out of the cancer cell. We have defined a novel role for P-gp in protecting cells against death induced by non-drug stimuli, where an efflux effect of P-gp would have no obvious benefit. This broader survival effec ....The ability of tumor cells to survive treatment by chemotherapy is a major obstacle in curing patients with cancer. One mechanism by which cancer cells become multidrug resistant (MDR) is their acquired expression of a protein called P-glycoprotein (P-gp) that extrudes cytotoxic drugs out of the cancer cell. We have defined a novel role for P-gp in protecting cells against death induced by non-drug stimuli, where an efflux effect of P-gp would have no obvious benefit. This broader survival effect of P-gp may be explained by its ability to regulate the activity of key enzymes (caspases) that exist within cells to induce cell suicide when appropriate. Many chemotherapeutic drugs activate caspases to kill target cells and as P-gp can inhibit caspase activation, it is therefore possible that P-gp affects the activity of anti-cancer drugs by both removing the drugs from the target cells and inhibiting the pathways through which the drugs can kill a cell. We have mutated P-gp to define the region that is necessary for its caspase regulatory function. We are now identifying the proteins that bind to this region so that we can determine how P-gp regulates caspase activation. In addition, we have defined the manner by which P-gp expression is kept low in normal cells and is upregulated following exposure of cells to chemotherapeutic drugs. The gene encoding P-gp (MDR1) is normally switched off due to the way it is packaged within a nuclear structure called chromatin. We have shown that treatment of cancer cell lines with chemotherapeutic drugs alters chromatin in such a way that the MDR1 gene is activated. We will identify the proteins and complexes involved in drug-mediated regulation of chromatin structure and determine if this phenomenon occurs within patients receiving chemotherapy. Our new findings may lead to novel treatment options for patients that have MDR cancers and may provide insight into possible new ways to inhibit the formation of P-gp-expressing MDR tumors.Read moreRead less
Non-viral Vectors For Targeted Delivery Of RNAi Nucleotides To Cervical Cancers
Funder
National Health and Medical Research Council
Funding Amount
$415,738.00
Summary
RNA interference (or gene silencing) is a new technique whereby we are able to turn off the expression of a particular gene either temporarily or permanently. Cancer is basically a genetic disease where certain protective genes are lost or cancer-causing genes expressed. Gene silencing holds great promise in the treatment of genetic disorders, infectious diseases and cancer. Cervical cancer is caused by infection with the human papillomavirus and the expression of two cancer-causing genes. Using ....RNA interference (or gene silencing) is a new technique whereby we are able to turn off the expression of a particular gene either temporarily or permanently. Cancer is basically a genetic disease where certain protective genes are lost or cancer-causing genes expressed. Gene silencing holds great promise in the treatment of genetic disorders, infectious diseases and cancer. Cervical cancer is caused by infection with the human papillomavirus and the expression of two cancer-causing genes. Using RNA interference we can turn off the expression of these two genes which results in the death of the cancer cell. We are also able to cure mice of tumours derived from human cervical cancer. The major issue with gene silencing is how to deliver it effectively to patients. Here we are investigating novel nanoparticulate systems to deliver this new gene-inhibiting drugs preferentially to the tumour site.Read moreRead less
BMP4 - A Metastasis Suppressor Gene In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$454,220.00
Summary
Breast cancer is the most common cause of cancer death in western women. Whilst the primary tumour can often be eradicated successfully, in many cases, it may have already spread to other organs, including lungs, liver and bone, causing severe morbidity. Current treatments are largely palliative and new therapies that specifically prevent to spread of breast cancer are urgently required. However, little is known about the molecular pathways regulating the spread of cancer cells. We have shown th ....Breast cancer is the most common cause of cancer death in western women. Whilst the primary tumour can often be eradicated successfully, in many cases, it may have already spread to other organs, including lungs, liver and bone, causing severe morbidity. Current treatments are largely palliative and new therapies that specifically prevent to spread of breast cancer are urgently required. However, little is known about the molecular pathways regulating the spread of cancer cells. We have shown that expression of a gene called BMP4 in tumours blocks the spread of breast cancer in a mouse model. The aim of this project is to develop the application of BMP4 as a therapy for advanced breast cancer using our mouse model. We will measure the expression of BMP4 in human breast cancer and test whether treatment with purified BMP4 protein can protect mice from the spread of breast cancer. If successful, this study will offer a new therapy for women with currently incurable breast cancer.Read moreRead less
EphA3-modulated Cell Positioning In Tumour Invasion And Neovascularisation.
Funder
National Health and Medical Research Council
Funding Amount
$647,232.00
Summary
During the progression of human cancers, tumor cells increasingly lose their ability to communicate and co-exist in a regulated fashion with normal cells to maintain the status quo. Because they multiply uncontrollably, tumour cells spread into surrounding tissue and can invade other organs of the body. The Ephs and interacting ephrins are proteins on the cell surface, and their communication controls the position of cells within the body tissues and organs, but also in tumours. Together with co ....During the progression of human cancers, tumor cells increasingly lose their ability to communicate and co-exist in a regulated fashion with normal cells to maintain the status quo. Because they multiply uncontrollably, tumour cells spread into surrounding tissue and can invade other organs of the body. The Ephs and interacting ephrins are proteins on the cell surface, and their communication controls the position of cells within the body tissues and organs, but also in tumours. Together with collaborators at the Ludwig Institute for Cancer Research and the Queensland Institute for Medical Research we produced two proteins, an antibody and a recombinant ephrin that bind one of the Eph proteins on tumour cells. The antibody allowed us to locate Eph in tumours, where it appears surprisingly not only on tumour cells but also on tumour blood vessels. When attached to a redioactive compund it selectively targets the cancer cells and in an animal study prolonged the survival of mice with leukemia significantly. We will now investigate the exact role of this Eph protein in tumour blood vessels. We will then study what happens in tumours when a toxic antibody-drug compound targets this tumour and starts to kill tumour cells. Finally, we will devise a novel reagent that combines the properties of the antibody with the properties of the ephrin into a single protein, which can deliver a cell-killing drug exclusively and most efficiently to tumour cells containing the Eph protein on its surface.Read moreRead less
Development Of Novel And Selective Anticancer Drugs Derived From Cysteine.
Funder
National Health and Medical Research Council
Funding Amount
$264,250.00
Summary
In the next few years cancer is projected to become the leading cause of death in industrialised countries. Cancer chemotherapy currently relies on destruction of tumours by toxic drugs that indiscriminately kill all cell types, resulting in side effects that limit treatment. In the 21st century new cancer drugs will more effectively destroy malignant tumour cells without damaging normal cells. The R and D herein will value-add to our discovery of a new class of potent and orally active anti-tum ....In the next few years cancer is projected to become the leading cause of death in industrialised countries. Cancer chemotherapy currently relies on destruction of tumours by toxic drugs that indiscriminately kill all cell types, resulting in side effects that limit treatment. In the 21st century new cancer drugs will more effectively destroy malignant tumour cells without damaging normal cells. The R and D herein will value-add to our discovery of a new class of potent and orally active anti-tumour drugs that possess unusually high selectivity in acting on cancer cells without killing normal human cells. Our current proof of concept will be turned into a drug development candidate that will improve our negotiating position with commercial partners.Read moreRead less
Molecular Epidemiology Of Ovarian Cancer: The Australian Ovarian Cancer Study National Clinical Follow-Up Core
Funder
National Health and Medical Research Council
Funding Amount
$883,244.00
Summary
Ovarian cancer is the seventh most common cancer in Australian women and fifth most common cause of cancer death, with approximately 1200 new cases diagnosed and 750 deaths each year. There is an urgent need to better understand the molecular, epidemiological and genetic characteristics of epithelial ovarian cancer and how these influence response to treatment and clinical outcome. Ovarian cancer is a histologically and clinically diverse disease and the variability in clinical outcome in ovaria ....Ovarian cancer is the seventh most common cancer in Australian women and fifth most common cause of cancer death, with approximately 1200 new cases diagnosed and 750 deaths each year. There is an urgent need to better understand the molecular, epidemiological and genetic characteristics of epithelial ovarian cancer and how these influence response to treatment and clinical outcome. Ovarian cancer is a histologically and clinically diverse disease and the variability in clinical outcome in ovarian cancer patients suggests that reliable predictive factors would be of clinical value. However, it is clear that the collection of hundreds of annotated biospecimens is essential if the interaction of genes and environment in the genesis of this disease is to be understood or the molecular features of this disease dissected. Recognizing that this can only be achieved through large-scale collaboration, the Australian Ovarian Cancer Study (AOCS) was established in 2000 by scientists from the Peter MacCallum Cancer Centre, the Queensland Institute for Medical Research, Melbourne University and Westmead Institute for Cancer Research in collaboration with clinicians across Australia. AOCS has recruited 1105 patients to date and this Research Proposal aims to complete the collection of clinical data on all AOCS patients nationally, to validate the use of microarray gene expression profiles to predict clinical outcome and to find genetic variants that may determine clinical outcome in individual patients. The creation of AOCS has provided a unique oportunity to collect one of the finest ovarian cancer biological sample sets in the world. We believe that this internationally significant study will shed light on the basis of response of ovarian cancer to treatment and provide an ongoing resource for research into the causes of ovarian cancer, and studies on the response to treatment.Read moreRead less
Molecular And Cellular Determinants Of Tubulin-targeted Drug Action
Funder
National Health and Medical Research Council
Funding Amount
$484,500.00
Summary
Cancer is the leading cause of death in developed countries. Despite advances in the use of combination chemotherapy, drug resistance is the major cause of treatment failure. An important component in the treatment of many childhood and adult cancers are the antimicrotubule agents. These drugs target an important part of the cell skeleton called the tubulin-microtubule system that is responsible for many important events including cell division. It is the ability of these drugs to disrupt cell d ....Cancer is the leading cause of death in developed countries. Despite advances in the use of combination chemotherapy, drug resistance is the major cause of treatment failure. An important component in the treatment of many childhood and adult cancers are the antimicrotubule agents. These drugs target an important part of the cell skeleton called the tubulin-microtubule system that is responsible for many important events including cell division. It is the ability of these drugs to disrupt cell division in cancer cells that makes them so effective and such important targets for new drug design. Unfortunately, the reasons why tumours develop resistance to these drugs or even why some tumours do respond well is not understood. This proposal will determine how the makeup and stability of the tubulin-microtubule proteins influences how these drugs work in both childhood and adult tumour cells. Finally, components of drug resistant tumour cells will be examined using technology that allows us to simultaneously separate and identify hundreds of proteins some of which may provide useful targets for the design of new drugs for the treatment of cancer. To improve cancer survival rates it is essential to accurately target the use of existing drugs and to identify new targets for anticancer drug development.Read moreRead less
A Clinical Trial Evaluating Neoadjuvant Chemotherapy For Women With Large Operable Or Locally Advanced Breast Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$269,805.00
Summary
Larger operable and locally advanced breast cancers (BC) which can involve the skin of the breast and lymph nodes under the arm are associated with poorer survival. Standard treatment usually includes neoadjuvant (or preoperative) chemotherapy to try to reduce the size of the cancer, followed by surgery and radiation therapy to treat any remaining cancer in the breast. Many women, despite maximum treatment, will still die from their disease, hence the need to develop more effective drug therapie ....Larger operable and locally advanced breast cancers (BC) which can involve the skin of the breast and lymph nodes under the arm are associated with poorer survival. Standard treatment usually includes neoadjuvant (or preoperative) chemotherapy to try to reduce the size of the cancer, followed by surgery and radiation therapy to treat any remaining cancer in the breast. Many women, despite maximum treatment, will still die from their disease, hence the need to develop more effective drug therapies. The advantages of neoadjuvant chemotherapy include: the potential to reduce the size of the breast cancer which may allow breast conserving surgery rather than mastectomy; and, the ability to directly assess the response of breast cancers to new drug treatments. This new research project aims to evaluate standard chemotherapy (epirubicin and cyclophosphamide) followed by a course of two newer, possibly more beneficial, chemotherapy drugs for breast cancer (docetaxel and gemcitabine (DG)) followed by surgery, in women with large operable-locally advanced breast cancer. The trial will allow patients with HER2 positive breast cancer to receive trastuzumab (Herceptin ) in addition to the DG chemotherapy treatment cycles. The study will measure the tumour response rates, efficacy and safety of the proposed treatments. Patients will be asked to consent to an extra core biopsy and a small sample of their breast tissue collected at the time of their breast surgery to be used for research to help better understand the biology of the disease and responses to treatment. The study could plausibly offer a better treatment for patients, resulting in a better prognosis for women who present with large operable or locally advanced breast cancer. The trial will be conducted, in Australia and New Zealand, by the Australian New Zealand Breast Cancer Trials Group (ANZ BCTG) and will involve approximately twenty Australian hospitals.Read moreRead less
Inhibition Of Breast Cancer Metastasis Through Targeting Of Laminin-10 Function
Funder
National Health and Medical Research Council
Funding Amount
$391,241.00
Summary
Breast cancer affects 1 in 11 women in Australia. Whilst breast cancer is highly curable when detected early, current treatments are ineffective when the disease has spread to other organs such as bone and lungs. Thus, novel therapies for the treatment of advance disease are urgently needed. We have found that laminin-10, a protein present in the breast and thought to control normal breast development and maturation, is particularly abundant in aggressive tumours as well as in those that have sp ....Breast cancer affects 1 in 11 women in Australia. Whilst breast cancer is highly curable when detected early, current treatments are ineffective when the disease has spread to other organs such as bone and lungs. Thus, novel therapies for the treatment of advance disease are urgently needed. We have found that laminin-10, a protein present in the breast and thought to control normal breast development and maturation, is particularly abundant in aggressive tumours as well as in those that have spread to bone and lungs suggesting that this protein may play a role in the dissemination of breast cancer cells to other organs. Consistent with this, we have found that laminin-10 stimulates breast tumour cell adhesion and movement in culture, two activities required for successful metastasis of tumour cells. The overall objective of the projects is to demonstrate that breast cancer metastasis can be inhibited by interefering with the function of laminin-10. To this end, we will measure the effect of blocking the production of LN-10 in breast tumour cells on their ability to metastasise. Alternatively, we will test fragments of laminin-10 for their ability to block laminin-10-induced tumour cell growth and movement (required for their escape from the breast) and viability (required for their establishment in distant organs). We will generate antibodies against the most inhibitory fragments and test their effect on spontaneous metastasis in a clinically relevant mouse model of breast cancer metastasis in an attempt to stop-reverse the progression of the disease. If successful, this project will provide the foundation for the development novel inhibitors targeting laminin-10 for the treatment of patients with advanced breast cancer.Read moreRead less