Interaction Of New Kinase Inhibitor Drugs With Multi-drug Resistance (MDR) Transporter Proteins.
Funder
National Health and Medical Research Council
Funding Amount
$411,000.00
Summary
Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, ....Multidrug transporter proteins are remarkable molecular pumps that expel a wide variety of drugs and toxins from cells. They are located at strategic sites where they eliminate harmful substances from the body or prevent them being absorbed from our diet in the first place. Multidrug transporters are also found at natural barriers within the body where they protect vulnerable tissue compartments, including the brain, cerebrospinal fluid, testes and, in preganant women, the foetus. Nevertheless, multidrug transporters sometimes interfere with drug therapy. They can prevent efficient absorption of drugs, increase the rate of drug elimination from the body, or prevent drug access to some tissues . Moreover, the activity of the transporters is quite variable, both between patients and within the same patient over time. This makes it difficult to provide optimal drug doses, particularly when treating cancer, where the drugs must be given at the maximum tolerated dose. The presence of drug transporter proteins in tumour cells can prevent entry of anticancer drugs, rendering them resistant to treatment. This is the main cause of failure in chemotherapy. This project will investigate a class of very promising new anticancer drugs, kinase inhibitors, to determine whether they are pumped by multidrug transporters, whether they alter the amounts of drug transporters in cells, and whether they alter transporter activity. We will also determine the consequences that follow from this for drug therapy. This information will help clinicians to rationally optimise therapy with the new drugs, to identify in advance both favourable (synergistic) and unfavourable (harmful) drug interactions in combination chemotherapy, to optimise drug doses and to minimise toxic side effects. The information will also add to our general understanding of drug absorption and elimination, and to the basic science of the remarkable multidrug transporter proteins.Read moreRead less
Destructive bone loss is a serious complication of many common inflammatory diseases. Three important examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent advances in the understanding of these diseases has allow us to better i ....Destructive bone loss is a serious complication of many common inflammatory diseases. Three important examples are are, periodontal disease, rheumatoid arthritis and peri-implant osteolysis. The mechanism of osteoclast formation in these diseases is distinctly different from physiologic osteoclast formation. Despite the prevalence of these diseases until recently little is known about how bone erosion occurs However, recent advances in the understanding of these diseases has allow us to better investigate the mechanisms of the bone loss. Drugs to stop the loss of bone have only recently been available to patients and many new treatments are being developed. While most of these drugs are proving useful to treat osteoporosis, their suitability for the treatment of bone loss in diseases such as periodontal disease, rheumatoid arthritis and peri-implant osteolysis is largely unknown. As the way bone is lost in these inflammatory diseases quite different from osteoporosis different treatments are needed. This project aims to better understand bone loss in these diseases and identify new treatments to prevent the debilitating bone loss associated with inflammation in disease.Read moreRead less
Development Of Anti-tropomyosin Drugs For The Treatment Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$578,352.00
Summary
Australia has the highest incidence of melanoma worldwide. There is a clear need to develop new strategies as melanoma is unresponsive to current treatment regimes. We have developed a compound, TR100, which targets a specific component of the cytoskeleton of melanoma tumour cells. Disruption of this cytoskeleton leads to decreased tumour cell growth and survival. Understanding the mechanism by which TR100 causes cell death is important if this novel anti-cancer compound is to be used in the cli ....Australia has the highest incidence of melanoma worldwide. There is a clear need to develop new strategies as melanoma is unresponsive to current treatment regimes. We have developed a compound, TR100, which targets a specific component of the cytoskeleton of melanoma tumour cells. Disruption of this cytoskeleton leads to decreased tumour cell growth and survival. Understanding the mechanism by which TR100 causes cell death is important if this novel anti-cancer compound is to be used in the clinic.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.
The Effect Of IL28B Haplotype On Hepatitis C Virus Infection And Treatment Response
Funder
National Health and Medical Research Council
Funding Amount
$525,576.00
Summary
About 3% of the world population is currently infected with hepatitis C virus (HCV). Most have chronic infection with a high risk for progressive liver fibrosis and subsequent liver cirrhosis and hepatocellular carcinoma. We have recently demonstrated genetic variants of the IL28B gene predict viral clearance with and without treatment after HCV infection. Determining why will impact on the development of new therapies, optimise use of current therapies, and identify patients who may respond to ....About 3% of the world population is currently infected with hepatitis C virus (HCV). Most have chronic infection with a high risk for progressive liver fibrosis and subsequent liver cirrhosis and hepatocellular carcinoma. We have recently demonstrated genetic variants of the IL28B gene predict viral clearance with and without treatment after HCV infection. Determining why will impact on the development of new therapies, optimise use of current therapies, and identify patients who may respond to alternative therapies.Read moreRead less
Molecular Characterisation Of The Glucagon-like Peptide 1 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$681,953.00
Summary
The glucagon-like peptide 1 receptor is a major target for treatment of Type 2 diabetes and obesity. However, the development of drugs for this receptor is challenging due to limited understanding of potential sites of drug interaction and how individual drugs may differentially change signalling from the receptor. This project will address these critical knowledge gaps, which may allow for improved therapeutic outcomes.
Multi-site Randomised Controlled Trial Of Fluoxetine In Children And Adolescents With Autism.
Funder
National Health and Medical Research Council
Funding Amount
$499,482.00
Summary
Fluoxetine is a medication that is increasingly used in children with autism in an attempt to control repetitive behaviours, which substantially interfere with daily functioning and quality of life. However clinicians working in the field of autism and goverment regulatory bodies (such as the TGA) require evidence of the efficacy of fluoxetine for this indication. This study aims to determine this, thereby addressing an important gap in clinical knowledge.
Nanopatch Immunisation Against Pandemic Influenza: Improved Immune Responses At A Reduced Dose.
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
Development of a new way to vaccinate against influenza that will make standard vaccines 100 times more potent than conventional syringe injection. The Nanopatch is made from a silicon wafer, bristling with micro-nanoscale spikes. It painlessly deposits vaccine under the skin surface. Experiments in mice show that even a small vaccine payload delivered to the skin generates good immune responses. The Nanopatch vaccination system is expected to be ready for clinical trials within a few years.
Bitopic Ligands As A Novel Approach To G-protein-coupled Receptor Selectivity
Funder
National Health and Medical Research Council
Funding Amount
$540,356.00
Summary
This project will focus on two important types of brain proteins that have been implicated in various symptoms associated with schizophrenia. The aim is to exploit a new paradigm of drug action that we have discovered, whereby novel compounds can be utilized to simultaneously target multiples sites on these brain proteins, in an effort to discover new mechanisms that can promote more selective signalling and, ultimately, can be used to design safer and more effective medicines.
Randomised, Double-blind, Placebo Controlled Trial Of Lithium Carbonate For The Management Of Human Cannabis Withdrawal
Funder
National Health and Medical Research Council
Funding Amount
$523,509.00
Summary
This project aims to help dependent cannabis users stop using cannabis by exploring the safety and effectiveness of lithium in reducing the severity of withdrawal that occurs on cessation of use. Participants will be admitted to an inpatient drug treatment unit (Sydney or Lismore) for 7 days and will be randomly assigned to receive either lithium or placebo. Participants receiving lithium are expected to have less severe withdrawal and higher rates of abstinence from cannabis at follow-up.