Biomarkers And EGFR Inhibitor Treatment Of Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$286,328.00
Summary
Non-Small Cell Lung Cancer (NSCLC) remains the most frequent cause of cancer death in the Australian population. This laboratory research will involve researchers across a number of centres in Australia. The research is focused on the effects of a new targeted cancer drug called cetuximab. The Epidermal Growth Factor Receptor (EGFR) pathway is an important cause of NSCLC in many patients, and this is blocked by cetuximab. The advent of new targeted cancer therapies, which block specific cancer p ....Non-Small Cell Lung Cancer (NSCLC) remains the most frequent cause of cancer death in the Australian population. This laboratory research will involve researchers across a number of centres in Australia. The research is focused on the effects of a new targeted cancer drug called cetuximab. The Epidermal Growth Factor Receptor (EGFR) pathway is an important cause of NSCLC in many patients, and this is blocked by cetuximab. The advent of new targeted cancer therapies, which block specific cancer pathways in the cell, has highlighted the need for detailed knowledge about how these therapies work at the molecular level, so that we can make best use of them. The laboratory studies will be on tissues taken from patients with NSCLC who are receiving chemotherapy then going on to surgery to have the cancers removed. Tumour samples will be taken prior to treatment, and then the surgical resection will also be analysed. Sequential blood samples will also be taken. Prior to surgery, patients will receive a 9 week course of chemotherapy with cisplatin and docetaxel to shrink the cancer. In addition, some patients will be randomised to receive cetuximab along with chemotherapy. In the laboratory, we will investigate whether various measures of activation of the EGFR pathway in the cancer and in blood predict for response to cetuximab. We will also investigate how the changes in tumour with cetuximab treatment differ from tumours not treated with the drug. We will be examining the genes and proteins of EGFR and those of a number of related pathways. a number of related receptor, along with From this we will attempt to understand which patients benefit most from the drug and also in what specific ways the cancer cells are affected by the treatment.Read moreRead less
Validating The NLRP3 Inflammasome As A Therapeutic Target In Motor Neuron Disease
Funder
National Health and Medical Research Council
Funding Amount
$780,249.00
Summary
There is no effective treatment for Motor Neuron Disease (MND). Two Australian’s die each day from MND, and 2 more are diagnosed. Modification of the immune system is one potential means of slowing MND. Our research team has identified a component of the immune system, which may be an ideal therapeutic target to treat this disease. Our project will test this therapeutic target in animal models of MND, and in human MND blood samples.
Immuno-polymeric Drugs For Prostate Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$626,995.00
Summary
Prostate cancer is the most common cancer in men over 50 and the second most frequent cause of cancer deaths in Western society. Docetaxel is the first line of chemotherapy when other intervention strategies are unsuccessful, but 30% of patients suffer from severe side-effects. To address this problem, we will utilise carriers for docetaxel that directly target prostate tumours using a novel antibody approach. This increases accumulation at the tumour site while decreasing off-target toxicity.
SiRNA Induced TGS Of Retroviruses: Elucidation Of Underlying Mechanisms And Their Application In Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$371,502.00
Summary
AIMS To elucidate changes in DNA that accompany suppression of HIV growth caused by certain unusual RNA molecules that turn off the ability of HIV to reproduce and make the virus dormant within the infected cell. While we have discovered RNA molecules that can do this to HIV in the test tube, we wish to develop similar molecules that can be used in animal models, so that we can decide whether this technology can be developed for use in humans. We also wish to understand more clearlky the mechani ....AIMS To elucidate changes in DNA that accompany suppression of HIV growth caused by certain unusual RNA molecules that turn off the ability of HIV to reproduce and make the virus dormant within the infected cell. While we have discovered RNA molecules that can do this to HIV in the test tube, we wish to develop similar molecules that can be used in animal models, so that we can decide whether this technology can be developed for use in humans. We also wish to understand more clearlky the mechanisms underlying this effect. BACKGROUND These RNA molecules can suppress a range of pathogenic human viruses including HIV-1 in the test tube. Our novel approach appears to induce changes that are long lasting and are less susceptible to mutations by the virus that allow it to become resistant to other therapeutic strategies. RESEARCH PLAN Initially more work will be done in tissue culture to determine the optimal design of these molecules and the best way to administer them. The most promising of these designs will be tested in small groups of infected animals as a preliminary demonstration of efficacy. In parallel experiments will be performed to elucidate the mechanisms undelying the suppressive effects of these molecules. OUTCOMES AND SIGNIFICANCE This work will lead to a significant increase in our understanding of the way replication of HIV is regulated and will develop a promising new therapeutic strategy for this virus that may be applicable to other conditions.Read moreRead less
Functional Analysis Of The Molecular Switch That Regulates ADAM10-mediated Cleavage Of RTK Ligands In Tumour Cells.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of th ....We have determined the structure and identified the region of the ADAM10 metalloprotease that controls its specific cleavage of ephrins. Ephrins and their receptors (Ephs) direct cell positioning during development by controlling cell-cell adhesion and repulsion. In adult tissues these proteins are present at low levels but are found at high levels in human cancers, including skin cancers, where they are thought to promote aggressive tumours. The switch to cell repulsion occurs by cleavage of the ephrin by ADAM10 which also functions in other cancer promoting events by cleaving growth factors. Our structure reveals how Eph-bound ephrin is specifically targeted by ADAM. We will now determine the relevance of this mechanism for other ADAM10 targets, and design drugs to bind this region and inhibit ADAM function, which we will test in assays measuring tumour cell movement and growth, with the aim of developing therapies to block cancer progression.Read moreRead less
Relaxin Receptor Structural Determination To Aid Therapeutic Development
Funder
National Health and Medical Research Council
Funding Amount
$1,249,114.00
Summary
The receptor for the peptide hormone relaxin, RXFP1, is being targeted by numerous drug companies for the treatment of cardiovascular disease. However, the lack of molecular detail of how relaxin binds and activates RXFP1 is hindering new drug development. We will determine the structure of the complex of relaxin bound to RXFP1 and the mechanism by which this activates cells. The knowledge gained will aid in the design of new drugs targeting RXFP1 for the treatment of cardiovascular disease.
Glucocorticoids (or 'steroids') are among the most commonly used drugs in the world, chiefly used for inflammatory diseases. However, they have major predictable side effects that have been known for over 60 years. Science has, til now, failed to deliver an alternative that delivers the effects of steroids without the side effects. This application is for funds to support the development of the discovery of the protein known as GILZ towards a treatment to help patients.
Targeting The Complement Cascade: A Novel Therapeutic Strategy For Metastatic Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$546,496.00
Summary
The incidence of melanoma is increasing world-wide, and Queensland has the highest rate of melanoma in the world. Despite advances in treatment, the 3-year survival rate for metastatic melanoma remains extremely low. This project builds on our recent research demonstrating a role for a key component of the innate immune system (complement C3a) in melanoma growth. Specifically we seek to investigate the potential of C3a as a therapeutic target for metastatic melanoma.