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Improving Immunotherapy By Vascular Targeting And Barrier Alteration
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
Tumors grow in part because they escape destruction by the immune system. New blood vessels grow inside tumors by a process called angiogenesis, which then stops cancer-fighting cells in their tracks. We hypothesise that breaking down the blood-tumor barrier will open tumors for attack by the cancer-fighting immune system. This proposal continues our work on reversal of angiogenesis in the context of immunotherapy. We expect these findings to lead to highly effective anti-tumor therapies.
Cellular And Molecular Mechanisms Of Human Choroidal And Retinal Vascularisation
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness h ....The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness has motivated the search for a better understanding of how blood vessel growth in the eye is controlled in healthy tissues and how these controls fail in disease. Our proposal addresses this issue directly. Recent work shows that this neovascularization is not only a response to a rise in the local concentration of molecules that induce such angiogenesis, but also requires a fall in the levels of endogenous molecules that inhibit angiogenesis. Our study will investigate the expression of newly identified angiogenic growth factors (VEGFs) and their receptors as well as angiogenic inhibitors (VEGI and PEDF) in the developing and adult human retina and choroid. We will examine the mechanisms by which the human choroid is formed. Our preliminary results suggests the novel insight that vasculogenesis (the formation of blood vessels via transformation of vascular precursor cells) plays a major role the formation of both the human retina and choroid. Further, these exciting results suggest involvement of novel growth stimulators and inhibitors previously not known to play a role in these processes. Our studies will lead to new insights regarding the vascular growth factors and inhibitors that drive this process, thus leading to a rational basis for new therapeutic targets for the treatment of ARMD. The rapid aging of the Australian population and the consequent predicted doubling of ARMD incidence in the next 20 years demonstrates the urgency of our studies.Read moreRead less
The Role Of RYK And Eph Receptors In Developmental And Tumour Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
The formation of blood vessels (angiogenesis) is a key process in development of the embryo, wound healing, tumour formation-metastases and in the re-vascularisation of ischeamic limbs. The molecules which control these processess are slowly being characterised. In general belong to a family of molecules called growth factors and theri associated receptor present on the surface of a cell. These molecules can control the number, location and function of specific blood vessels within the body. Rec ....The formation of blood vessels (angiogenesis) is a key process in development of the embryo, wound healing, tumour formation-metastases and in the re-vascularisation of ischeamic limbs. The molecules which control these processess are slowly being characterised. In general belong to a family of molecules called growth factors and theri associated receptor present on the surface of a cell. These molecules can control the number, location and function of specific blood vessels within the body. Recently we have discoverd new members of a family of growth fcators called vascular endothelial growth factors, and demonstrated their ability to promote the growth of blood and lymphatic vessels. In this study we set out to examine the role of another family of growth factor receptors, called RYK (for which we have a granted patent in the USA and Australia) in angiogenesis. functional experiments in mice have demonstrated that RYK can associated with a family of receptors called Eph receptors which play a key role in the remodelling of blood vessels during development and injury. Studying these molecules may tell us why blood vessels know' to be in the correct locations in the body and why in certain disease we see vessels of incorrect structure or location. These studies will form a basis of knowledge to develop rational means to manipulate blood vessel formation in the body, using non-surgical methods. The work will also have application to the areas of cleft palate, craniofacial abnormalities and axon pathfinding.Read moreRead less
Charged Lipophilic Dendrimers: Delivery Of Oligonucleotides With Therapeutic Potential
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
Summary
Choroidal neovascularisation, which is the most severe form of Age Related Macular Degeneration (AMD) is the major cause of blindness in the developed world. The disease usually affects people above the age of 75-80. With an ageing population, reaching 3.5 million (over 65) in Australia by year of 2020, AMD is quickly becoming a significant socio-economic problem. Gene therapy could be a cure for the above disease. Currently, there are large numbers of antisense oligonucleotides that have the po ....Choroidal neovascularisation, which is the most severe form of Age Related Macular Degeneration (AMD) is the major cause of blindness in the developed world. The disease usually affects people above the age of 75-80. With an ageing population, reaching 3.5 million (over 65) in Australia by year of 2020, AMD is quickly becoming a significant socio-economic problem. Gene therapy could be a cure for the above disease. Currently, there are large numbers of antisense oligonucleotides that have the potential to be developed as new medicines. However, a lack of absorption-cellular uptake and poor in vivo stability are major hurdles that must first be overcome, before any of these compounds will reach the clinic. Synthetic DNA delivery agents are of interest for gene therapy as an alternative to viral vectors, since they carry potentially fewer risks in terms of immuneresponse and propagation. Gene transfer with synthetic compounds is a growing field of research and the largest family of such agents is based on positively charged lipids which are able to self-associate and to form complexes (salts) with DNA conferring a compacted state on the plasmid. Our project will address these major issues through a highly novel strategy involving ion pair formation of lipophilic dendrimer (tree-like compounds with positive charges on the surface) constructs. This multidisciplinary approach has the potential to develop and test new DNA-dendrimer complexes and test them in a well established animal model for neovascularisation. Successful completion of this project might offer a potential therapy for choroidal neovascularisation, with a good chance of entering into human clinical trials by year 2004.Read moreRead less
Investigation Of A Tumour Enzyme As A Predictor Of Patient Response To An Australian Anti-cancer Drug
Funder
National Health and Medical Research Council
Funding Amount
$362,082.00
Summary
GSAO is a new cancer drug we have developed that is currently being trialed in cancer patients. Our investigation of how GSAO works has revealed that it needs to be activated by an enzyme expressed by certain types of cancers. This finding implies that GSAO should be more effective against cancers that make this enzyme. Our aim is to establish this concept in laboratory based experiments as a basis for selection of patients who are more likely to benefit from GSAO treatment.
NADPH Oxidase In Pathological Angiogenesis In Solid Tumours And Retina
Funder
National Health and Medical Research Council
Funding Amount
$581,989.00
Summary
Understanding blood vessel growth has profound clinical implications for many diseases. Blocking vessel growth is a promising strategy for treatment of cancer and eye complications accompanying diabetes, whereas treatments to stimulate new vessel growth will treat ischemic disorders ie. heart attack and stroke. Here we investigate whether targeting an enzyme that grows blood vessels has potential for making drugs to stop tumor growth or eye damage that occurs with diabetes and premature births.
There is an ongoing need for the development of new anticancer drugs, particularly those directed against solid tumours. In the past plants have been an extremely valuable source of anticancer agents, including the world s best selling anticancer drug, Taxol, isolated from the Pacific Yew tree. However, such molecules are typically complex and often very expensive to manufacture or extract from natural sources. So far very little attention has been paid to protein-based molecules from plants as ....There is an ongoing need for the development of new anticancer drugs, particularly those directed against solid tumours. In the past plants have been an extremely valuable source of anticancer agents, including the world s best selling anticancer drug, Taxol, isolated from the Pacific Yew tree. However, such molecules are typically complex and often very expensive to manufacture or extract from natural sources. So far very little attention has been paid to protein-based molecules from plants as potential anticancer agents because pharmaceutical companies have focused on organic molecules. In principle protein-based molecules could be produced much more cheaply and thus made available more widely to patients than existing drugs. All that is required are the lead molecules, or proteins that display sufficient anticancer activity to be used as the basis for further optimization. We have discovered a family of plant proteins called the cyclotides that have recently been shown to have considerable promise as anticancer agents. In the current project we will use synthetic chemistry to modify selected amino acids on the surface of this new family of proteins to determine which parts of the molecules are responsible for their activity. We will use this information to design improved analogues. The project is a collaboration between researchers at the Institute for Molecular Bioscience, University of Queensland, who have expertise in the required peptide chemistry and researchers and clinicians at Uppsala University, Sweden who have a range of assays and clinical expertise to test the new molecules. Both groups have been centrally involved in the discovery of the cyclotide family of plant proteins and are committed to developing them as exciting new anticancer agents.Read moreRead less