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MICROFABRICATED DEVICES: A SIGNIFICANT ADVANCE FOR THE DETECTION AND MOLECULAR ANALYSES OF CIRCULATING CANCER CELLS?
Funder
National Health and Medical Research Council
Funding Amount
$422,107.00
Summary
Using advanced microfabrication concepts, this project aims to develop a platform technology able to capture tumour cells circulating in the blood of cancer patients. Although present only in extremely small numbers, these cells provide invaluable insights into the pathophysiology of the disease and consequently provide vital diagnostic and prognostic information. Molecular analyses of these cancer cells could ultimately enable the design of improved and personalized cancer treatment.
Rational Design And Development Of New Anthracenedione Derivatives
Funder
National Health and Medical Research Council
Funding Amount
$471,702.00
Summary
Our laboratory has discovered a way to activate the anti-cancer drug mitoxantrone to make it bind to DNA more effectively. This involves pre-activating it with the simple molecule formaldehyde. This concept has enabled us to design new anticancer drugs that are predicted to be more effective at killing cancer cells. In this study we will synthesise these new compounds then test how effectively they bind to DNA, inhibit growth of tumour cells in culture, and inhibit growth of tumours in mice.
Development And Evaluation Of Biological Reagents Targeting And Inhibiting Function Of The EphA3 Receptor On Tumor Cells
Funder
National Health and Medical Research Council
Funding Amount
$490,500.00
Summary
Eph receptors and their ligands regulate morphogenesis in the embryo; they direct migration and positioning of cells during the formation of tissue layers and organ systems. There is little evidence for a function of Ephs in adult tissues. However, their abundant, un-scheduled occurrence in various malignant tumours, indicates a role in cancer. Human EphA3, the principle subject of this proposal, is not found in adult tissue but is present at high levels in lung, kidney and brain tumours, leukem ....Eph receptors and their ligands regulate morphogenesis in the embryo; they direct migration and positioning of cells during the formation of tissue layers and organ systems. There is little evidence for a function of Ephs in adult tissues. However, their abundant, un-scheduled occurrence in various malignant tumours, indicates a role in cancer. Human EphA3, the principle subject of this proposal, is not found in adult tissue but is present at high levels in lung, kidney and brain tumours, leukemia and malignant melanoma. High levels of EphA3 and corresponding ligands correlate with melanoma progression, and EphA3 stimulation triggers repulsion and detachment of melanoma cells. It is likely that Eph A3 is involved in release and spreading of tumour cells during melanoma progression. We have characterised reagents, the soluble EphA3 ligand and a monoclonal anti-EphA3 antibody, which bind EphA3 with high affinity and specificity. We will use these two proteins, or modified forms containing attached radiochemicals or cytotoxins, to target human tumours that were implanted into into immuno-deficient mice as animal model system. Our studies will determine if the specificity of our reagents, suggested from previous in-vitro studies, will allow imaging of EphA3 containing tumours, and effect their targeted killing. We will also use a tissue culture model, containing artificial epidermal and dermal layers of skin cells, to study if an inhibitory form of the EphA3 ligand will affect the invasiveness of EphA3 positive, metastatic melanoma cells. Furthermore, we will identify essential parts of this ligand to develop inhibitors with improved pharmacological properties. Together, our studies will establish the role for EphA3 in cancer progression and to assess the efficacy of EphA3 targeting for tumor killing and prevention of metastasis. We envision that this will provide the groundwork for Eph-specific reagents with anti-metastatic action in cancer therapy.Read moreRead less
Targeting Polymyxin-resistant Gram-negative Superbugs: Development Of Novel Antimicrobial Lipopeptides
Funder
National Health and Medical Research Council
Funding Amount
$661,069.00
Summary
Prevalence of resistance to antibiotics among Gram-negative 'superbugs' is a major global medical challenge, which is highlighted by the Bad Bugs, No Drugs campaign of the Infectious Diseases Society of America. There are virtually no new antibiotics in the current drug development pipeline for these dangerous pathogens. In this project, novel lipopeptides will be designed, synthesised and evaluated against these 'superbugs'. Information obtained will be crucial for further drug development.
Radiostereometric Analysis Of The Effect Of A Large Articulation On Prosthetic Wear And Migration After Hip Replacement
Funder
National Health and Medical Research Council
Funding Amount
$192,186.00
Summary
At total hip replacement, there has been a recent trend to use prostheses with a larger ball and liner in the socket. This may decrease the risk of post-operative dislocation, but may also increase the amount of wear, leading to bone loss and loosening of prostheses, which may then require replacement. This project will use a special type of x-ray to determine whether wear and movement of these new prostheses is clinically acceptable, so that they can be used with confidence in patients.
Improved Ways To Study The Effect Of Transient Exposures On The Risk Of An Illness, With Application To Flying And DVT
Funder
National Health and Medical Research Council
Funding Amount
$212,250.00
Summary
Improved methods of analysis will be developed to estimate the extent to which certain short-term activities trigger a particular illness and to determine who is most at risk. The new methods of analysis have many potential applications, including study of the effect of periods of intense exercise or intense alcohol consumption on the risk of a heart attack. Here we apply them to study the effect of air travel on illness due to blood clots in a vein (deep vein thrombosis, DVT), and the factors t ....Improved methods of analysis will be developed to estimate the extent to which certain short-term activities trigger a particular illness and to determine who is most at risk. The new methods of analysis have many potential applications, including study of the effect of periods of intense exercise or intense alcohol consumption on the risk of a heart attack. Here we apply them to study the effect of air travel on illness due to blood clots in a vein (deep vein thrombosis, DVT), and the factors that put individuals at greatest risk. The extra understanding that our improved analysis of the data provides will accelerate research into ways to minimise the risk of flight-induced DVT and implementation of preventative measures in the travel industry. This has the potential to prevent many cases, and deaths, because the number of flights taken, globally, by individuals in a year is now in the billions. Specifically, dependence of flight-induced DVT on age, sex, being pregnant, recent fractures and having certain cancers will identify individuals at greatest risk, while dependence on the duration of the flight will identify flights that present greater risk. The development of these new methods of analysis will make a lasting contribution to public health research, because they can be used to study many short-term-activity - illnesses combinations. The methods will see increasing applications because the type of data they rely on, namely the complete history of exposures over time periods, will increasingly become available as electronic recording of activities becomes more common place. For example, electronic records of flights are now almost universal and bookings at squash courts and other sporting venues are increasingly recorded electronically. The computer software to apply the new methods of analysis will be made available to other researchers, to promote studies of this type.Read moreRead less
Development Of A Health-related Quality Of Life Instrument For Children With Cerebral Palsy
Funder
National Health and Medical Research Council
Funding Amount
$114,000.00
Summary
This project aims to develop and test a measure of quality of life for children with cerebral palsy (CP). This is a new project of international significance that has been recommended as the highest research priority of the United Cerebral Palsy Association with the strong support of CP researchers and clinicians internationally. CP remains the most common cause of physical disability in childhood, with an incidence of 2-2.0-2.5 per 1,000 live births. Described as a 'non-progressive motor impair ....This project aims to develop and test a measure of quality of life for children with cerebral palsy (CP). This is a new project of international significance that has been recommended as the highest research priority of the United Cerebral Palsy Association with the strong support of CP researchers and clinicians internationally. CP remains the most common cause of physical disability in childhood, with an incidence of 2-2.0-2.5 per 1,000 live births. Described as a 'non-progressive motor impairment of central origin recognised in infancy or childhood', CP presents as a static lesion on the brain characterised by progressive muscoskeletal deformity. Its impact on children and families is profound, resulting in extensive and life-long burden of care for families, and significant limitations to children's development and wellbeing. The management of the neuromuscular sequelae and health problems is a considerable cost to the health system because children require frequent visits for medical management, surgical procedures and rehabilitation. Trials of CP management effectiveness are hampered by the absence of patient outcome measures. Whilst new treatment options aim to provide substantial improvements in impairment and functioning they have disadvantages. For example, spasticity management includes Botulinum toxin A and intrathecal baclofen, both may improve function but are costly and invasive; treatments for ambulation (multi-level orthopaedic surgery) offer improved gait and mobility but require extensive rehabilitation; treatments for severe eating difficulties and poor growth (gastrostomy) may improve survival but result in aggravation of gastro-oesophageal reflux; and surgery for intractable epilepsy may improve seizure disorder but result in functional deficits. Quality of life is now a mandatory component of clinical trial research; valid and reliable tools sensitive to detecting change are urgently required.Read moreRead less
Development Of Drug-loaded Antibody-targeted Nanoparticles To Kill Colorectal Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$513,146.00
Summary
COLORECTAL CANCER (CRC) is the most common cancer in the Western world. In Australia, the five-year survival rate after surgical resection of the primary lesion is 55%, and for patients with advanced disease the five-year survival rate is less than 10%. Colorectal cancer is relatively resistant to radiotherapy and chemotherapy and therefore there is great emphasis on identifying alternative modes of treatment. One approach that is attracting considerable attention is IMMUNOTHERAPY. In particular ....COLORECTAL CANCER (CRC) is the most common cancer in the Western world. In Australia, the five-year survival rate after surgical resection of the primary lesion is 55%, and for patients with advanced disease the five-year survival rate is less than 10%. Colorectal cancer is relatively resistant to radiotherapy and chemotherapy and therefore there is great emphasis on identifying alternative modes of treatment. One approach that is attracting considerable attention is IMMUNOTHERAPY. In particular, the A33 ANTIBODY system appears to have the potential to target colorectal cancer cells and achieve therapeutic outcomes. The A33 system has been well characterised in both a clinical and laboratory setting over the last few years and recent clinical trials with humanised versions of the A33 antibody have demonstrated rapid localisation and accumulation of radiolabelled A33 to colorectal cancer lesions. The application of NANOTECHNOLOGY to biological systems is likely to transform the way we treat a variety of diseases over the course of the next decade. Nanosized drug delivery vehicles have the potential to revolutionise the treatment of a number of diseases, cancer in particular. Hollow capsules can be synthesised with a drug sequestered inside the capsule, where the capsule wall performs a dual role of protecting the body from potentially harmful side effects of the drug, as well as protecting the drug from being degraded by the body. We plan to use these nanosized drug carriers, functionalised with the A33 antibody, to deliver chemotherapy agents directly to the colorectal cancer cells. We have recently demonstrated that in vitro, nanocapsules functionalised with the A33 antibody specifically bind to CRC cells, and once bound, the capsules are internalised. In this proposal we will test the ability of these particles to kill CRC cells in mice harbouring human tumours.Read moreRead less
Throughout our lives cells must die and be replenished. One way multicellular organisms remove unwanted cells is through a process called programmed cell death. This process eliminates redundant, damaged or infected cells by a program of cell suicide. We are studying the underlying molecular mechanisms of this cell suicide in order to design new pharmaceuticals to treat illnesses caused by a disruption in programmed cell death. The fine balance between living and dying cells must be maintained a ....Throughout our lives cells must die and be replenished. One way multicellular organisms remove unwanted cells is through a process called programmed cell death. This process eliminates redundant, damaged or infected cells by a program of cell suicide. We are studying the underlying molecular mechanisms of this cell suicide in order to design new pharmaceuticals to treat illnesses caused by a disruption in programmed cell death. The fine balance between living and dying cells must be maintained and if this balance is lost then disease may result. A reduced level of cell death may result in cancers while too many dying can contribute to degenerative diseases such as Alzheimer's disease and stroke. Currently many of these diseases do not have effective treatments. We will determine the three-dimensional structures of key proteins involved in programmed cell death and use this information to design drugs that can interfere with the molecular processes involved in signalling cell death. Such drugs may prove useful new therapies in a wide range of diseases caused by a breakdown in the biochemical paths to cell death.Read moreRead less
Structure-based Design Of Inhibitors Of Oxidative Protein Folding In Enterobacteriaceae.
Funder
National Health and Medical Research Council
Funding Amount
$523,540.00
Summary
Antibiotic resistance represents a major public health problem. For gram-negative bacteria in particular, the situation is increasingly bleak, with the accumulation of resistance to existing drugs and few if any new drugs in the pipeline. We are using structure-based drug design to develop novel strategies for the treatment of gram-negative bacterial infections.