The Role Of Intracellular Uptake And Retention Of Abl Kinase Inhibitors In Modifying Clinical Response In CML
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Imatinib is one of the first targeted anticancer drugs to be clinically developed. It is designed to inhibit the kinase activity of BCR-ABL, a mutant protein found in some cases of leukaemia, particularly chronic myeloid leukaemia. Blocking the kinase activity of BCR-ABL has proven to be highly effective therapy for most patients, achieving prolonged remissions and significantly improving survival. However resistance to imatinib is a problem, including failure to respond to imatinib, loss of res ....Imatinib is one of the first targeted anticancer drugs to be clinically developed. It is designed to inhibit the kinase activity of BCR-ABL, a mutant protein found in some cases of leukaemia, particularly chronic myeloid leukaemia. Blocking the kinase activity of BCR-ABL has proven to be highly effective therapy for most patients, achieving prolonged remissions and significantly improving survival. However resistance to imatinib is a problem, including failure to respond to imatinib, loss of response, and long term persistence of low levels of leukaemia. New ABL kinase inhibitors (AKIs) have been developed that are more potent than imatinib, but they also appear to be prone to resistance. One potentially important cause of resistance to AKIs is the ability of some leukaemic cells to modify their cellular pathways to reduce the effective concentration of the drug by either reducing its movement into the cell (influx) or increasing its movement out (efflux). We will investigate the mechanisms used by resistant leukaemic cells to reduce intracellular drug levels of these AKIs and test ways of countering these effects by blocking the proteins responsible for drug efflux or promoting drug influx. These studies will use our stored collections of leukaemic cells from responsive and resistant patients to determine the importance of specific influx and efflux pumps. It will help to identify patients where this form of resistance is limiting response. This may allow us to develop more effective AKIs that are less prone to these forms of drug resistance. We will also test whether other anti-cancer drugs have an impact on AKI drug transport because this could reduce the effectiveness of combination treatment. The effects on drug transport of concomitant administration of commonly used drugs together with AKIs will also be studied because this can reduce the effectiveness of AKis or in some cases improve their effectiveness by increasing their uptake and retention.Read moreRead less
Targeted Inhibition Of Polyamine Synthesis For Treatment Of Childhood Neuroblastoma
Funder
National Health and Medical Research Council
Funding Amount
$576,605.00
Summary
The childhood cancer, neuroblastoma, frequently has a dismal outcome despite the use of intensive therapy. Polyamines are molecules that are essential for cell survival and these are increased in aggressive neuroblastoma. Using pre-clinical models, we have shown that inhibiting polyamine production can significantly delay neuroblastoma growth. This project aims to improve the overall efficacy of this treatment by targeting multiple steps in polyamine synthesis in combination with chemotherapy.
Targeting Histone Deacetylases To Overcome Resistance Of BRAFV600E Melanoma Cells To Apoptosis
Funder
National Health and Medical Research Council
Funding Amount
$353,140.00
Summary
Results from early clinical studies with a new class of drugs in the treatment of melanoma have been very encouraging, but most tumors initially respond to the drugs regrow after short periods. We have recently shown that this is mainly related to resistance of melanoma cells to cell death induced by the drugs. In this project, we aim to explore a novel approach to overcome this resistance. If successful, the results will lead to new approaches in the treatment of melanoma.
Malaria is a very important disease worldwide, causing hundreds of millions of cases and about two million deaths per year. Severe malaria including cerebral malaria is a major cause of death. It is caused by red blood cells which contain malaria parasites sticking to the lining of microscopic veins and clogging them; what happens after this is complex. The process of sticking is called cytoadherence. We have discovered a gene which is important in this process of sticking. We have called it by ....Malaria is a very important disease worldwide, causing hundreds of millions of cases and about two million deaths per year. Severe malaria including cerebral malaria is a major cause of death. It is caused by red blood cells which contain malaria parasites sticking to the lining of microscopic veins and clogging them; what happens after this is complex. The process of sticking is called cytoadherence. We have discovered a gene which is important in this process of sticking. We have called it by the acronym clag, for cytoadherence-linked asexual gene; most Australians know of Clag as a glue. Our evidence for this has been accepted for publication by the prestigious USA journal Proceedings of the National Academy of Sciences of the USA. Recent work overseas aimed at determining the entire DNA sequence of the malaria parasite has shown that clag is not alone; there are at least 9 slightly different clag genes in the malaria parasite. What do the others do? We propose two possibilities. The first is that all of them act in cytoadherence but that different clags enable the parasitised cells to stick to different things on the lining of veins. The second is that they enable the parasitised cells, or perhaps the parasites alone, to stick to other things at different stages of the complex life cycle of the parasite. The experiments that we propose should show whether either of these proposals is true.Read moreRead less
Targeting Critical Nodes On The IGF1-PI3K Pathway To Improve Function Of The Failing Heart
Funder
National Health and Medical Research Council
Funding Amount
$512,947.00
Summary
Heart failure is a major clinical problem which is becoming worse as our population grows older and comorbidities such as obesity and diabetes become more prevalent. Current heart failure therapeutics largely delay disease progression. This research proposal focuses on strategies designed to improve function of the failing heart, as opposed to simply delaying disease progression. This approach will lead to the development of new therapeutics.
The Clag Gene Family Of P. Falciparum; Examining Roles In Cytoadherence, Rheological Properties Or Tissue Trophism.
Funder
National Health and Medical Research Council
Funding Amount
$451,980.00
Summary
There are approximately 500 million of cases of malaria per year worldwide and about two million deaths per year. Severe malaria including cerebral malaria is a major cause of death. It is caused by the sticking of red blood cells which contain malaria parasites to the lining of microscopic veins and blocking them; what happens after this is complex. The process of sticking is called cytoadherence. We have discovered a gene which is important in this process of sticking. We have called it by the ....There are approximately 500 million of cases of malaria per year worldwide and about two million deaths per year. Severe malaria including cerebral malaria is a major cause of death. It is caused by the sticking of red blood cells which contain malaria parasites to the lining of microscopic veins and blocking them; what happens after this is complex. The process of sticking is called cytoadherence. We have discovered a gene which is important in this process of sticking. We have called it by the acronym clag, for cytoadherence-linked asexual gene. Most Australians know of clag as a glue, and our data provides evidence that it sticks the parasitised red cells to veins via a protein called CD36 on the internal surface of veins. Our evidence for this has been published in two prestigious international journals. We propose here to examine the same gene in a mouse malaria model as it should be highly informative to see what effect destoying clag has on the disease in a living animal. Obviously this cannot be tested in people. It has now become clear that there are a number of slightly different clag genes and we do not know what the others do. We propose here that they may enable the parasitised red cells to stick to targets other than CD36 on the surfaces of veins, or affect blood flow of infected cells, or direct the parasitised red cells to other organs. The experiments that we propose should reveal whether these ideas are true.Read moreRead less
Improving Cancer Therapy: Nanoparticle Delivery Of SiRNA To Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$610,499.00
Summary
Lung cancer accounts for 8000 diagnosis and 1000 deaths in Australia each year. We are using cutting edge nanotechnology and coupling this with potent gene silencing to target solid tumours of the lung. If successful, this approach could increase survival of patients with this difficult to treat malignancy and may prove valuable in the treatment of other lung tumours.
Combined Novel Tumour-targeted Molecular And Traditional Chemotherapy For Treating Androgen Refractory Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$551,398.00
Summary
Consistent with Cancer Australia and PCFA priorities, in preclinical studies we will evaluate triple therapy for advanced prostate cancer.The three treatments to be tested together are adenoviruses, gene therapy and docetaxel, each of which has therapeutic potential individually. The combination should increase therapeutic effiacy and decrease the doses required, thus reducing side effects and increasing quality of life. Results obtained should enable translation to a clinical trial.