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LIM KINASE 1 (LIMK1) AND METASTASIS, THE SEARCH FOR LIMK1 INHIBITORS
Funder
National Health and Medical Research Council
Funding Amount
$461,250.00
Summary
Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. Importantly, we have demonstrated that (1) inhibiting LIMK1 blocks the formation of metastatic ....Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. Importantly, we have demonstrated that (1) inhibiting LIMK1 blocks the formation of metastatic tumours in mice, and (2) introduction of this protein into tumour cells makes them more invasive. In addition, we find that the level of LIMK1 is much higher in human tumour cell lines that have the propensity to easily form tumours in mice. Also, measuring the level of this protein in cancer cells that spread to other organs shows that it is at significantly elevated levels when compared to normal tissue. The goals of this research are to: (1) understand whether the ability of LIMK1 to regulate tumour spreading and invasiveness correlates with its ability to control metastasis; (2) examine in human tumour samples whether the levels of LIMK1 correlate with the development of metastatic tumours; and (3) search for drugs that can inhibit the activity of this protein. The results from this research will be highly significant because LIMK1 levels are likely to be an important marker for which tumours will become metastatic. It is possible that, at the time of tumour diagnosis, LIMK1 measurements will enable the clinician to predict whether an individual tumour will become metastatic. Secondly, this protein is a novel drug development target. Drugs that inhibit this protein may block the ability of tumours to invade and metastasise.Read moreRead less
Development Of Anti-metastatic And Tumour Targeting Reagents By Design Of Inhibitors To Specific Eph/ephrin Cell-cell
Funder
National Health and Medical Research Council
Funding Amount
$200,000.00
Summary
Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (E ....Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (Ephs) and their membrane-bound ephrin ligands are crucial mediators of cell adhesion and motility and are notably overexpressed in metastatic tumours rather than primary (benign) lesions5. Our laboratories were the first to identify EphA3 7, and one of the first to isolate its ligand, ephrin-A5. EphA3 was isolated from acute lymphoblastoid leukemia and malignant melanoma patients, where increasing expression levels correlate with metastatic progression. Soluble, non-clustered forms of Ephs and ephrins are effective inhibitors of Eph activity 3 and provide opportunities to generate specific drugs for cancer therapy. We now propose a research and development program for the development of EphA3-specific drugs and their production for pre-clinical and clinical evaluation for placement onto a national and international market.Read moreRead less
Stage II In The Development Of Eph/ephrin Based Tumor Targeting Reagents: Optimisation Of Drug Efficacy And Delivery
Funder
National Health and Medical Research Council
Funding Amount
$204,125.00
Summary
In the final stage of cancer, including melanoma, tumor cells gain the ability to spread, a process called metastasis. Altered communication between cancer and normal cells is one of the causes of this invasive characteristic. We have started the development of novel agents that target and modulate proteins on the cell surface that control these properties and are found in metastatic tumors. We propose to refine the targeting and killing properties of these agents for early clinical testing.
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
Regulation Of Signal Transduction By Cbl: Investigation Of Effects On The Cytoskeleton, Cell Adhesion And Cell Motility
Funder
National Health and Medical Research Council
Funding Amount
$256,527.00
Summary
Changes in cell adhesion and motility have been implicated in a wide range of human pathologies (e.g. immune, reproductive, mental, and cancerous disorders) . Cell adhesion and motility are tightly regulated by a group of proteins known as Rho-GTPases. Novel pharmacological agents that target signalling by Rho-GTPases have been demonstrated to profoundly affect tumour metastasis, as well as central nervous system regeneration following injury. Further exploitation of Rho-GTPase signal modulation ....Changes in cell adhesion and motility have been implicated in a wide range of human pathologies (e.g. immune, reproductive, mental, and cancerous disorders) . Cell adhesion and motility are tightly regulated by a group of proteins known as Rho-GTPases. Novel pharmacological agents that target signalling by Rho-GTPases have been demonstrated to profoundly affect tumour metastasis, as well as central nervous system regeneration following injury. Further exploitation of Rho-GTPase signal modulation, by detailed studies of the molecular mechanisms involved, could lead to significant advances in medical sciences. In particular, treatment of cancer and spinal injuries are likely to benefit from further development of Rho-signalling research.Read moreRead less
Development Of An In Vivo Pharmacokinetic-pharmacodynamic Model For Evaluation Of Antimalarial Drug Therapy Combinations
Funder
National Health and Medical Research Council
Funding Amount
$120,604.00
Summary
The World Health Organization currently estimates that there are 300-500 million cases of malaria annually, with 1.5-2.7 million deaths. These are staggering data, given that almost 20 antimalarial drugs are now in regular clinical use. Multi-drug resistance is present in most tropical countries where malaria is endemic and there has been a rapid escalation in cases of malaria in developed countries over recent decades (imported by travellers). Clearly, there is a need to ensure that current and ....The World Health Organization currently estimates that there are 300-500 million cases of malaria annually, with 1.5-2.7 million deaths. These are staggering data, given that almost 20 antimalarial drugs are now in regular clinical use. Multi-drug resistance is present in most tropical countries where malaria is endemic and there has been a rapid escalation in cases of malaria in developed countries over recent decades (imported by travellers). Clearly, there is a need to ensure that current and new treatment and prevention strategies are rational and effective. This project is based on the premise that improvements can be made in the in vitro testing process of antimalarial drugs. The experiments will be conducted using mice and a form of malaria that is specific to mice but closely resembles human malaria. In the first stage, the relationship between the amount of a new antimalarial drug (dihydroartemisinin) in the body and the effectiveness of the dose will be tested. These experiments will be repeated using conventional antimalarial drugs such as mefloquine. Information from these studies will subsequently be used to evaluate combinations of antimalarials. The results will be used as the basis of extensive, collaborative clinical studies in South-East Asia that are beyond the scope of this project. The methods used for this research will be important for future testing of new antimalarial drugs or combinations of drugs for the treatment and prophylaxis of malaria.Read moreRead less
I am a lab-based neurochemist-cell biologist with expertise in protein chemistry and pharmacology. My research focuses on the dynamin family of proteins in the endocytosis of synaptic vesicles and in the molecular mechanisms of synaptic transmission in th