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
Use Of Retroviral Expression Libraries To Characterise Mechanisms Of Drug Resistance In Leukaemia.
Funder
National Health and Medical Research Council
Funding Amount
$362,545.00
Summary
At present, treatment of leukaemia is based either on established chemotherapeutic drug treatment or newly identified inhibitor drugs currently being tested as part of clinical trials. Both these treatments are known to induce or select for resistance to the drugs in some cases. Resistance usually reduces the success rate of any further treatment with the same or similar drugs. To discover possible ways of overcoming drug resistance it is important to understand the mechanisms that are responsib ....At present, treatment of leukaemia is based either on established chemotherapeutic drug treatment or newly identified inhibitor drugs currently being tested as part of clinical trials. Both these treatments are known to induce or select for resistance to the drugs in some cases. Resistance usually reduces the success rate of any further treatment with the same or similar drugs. To discover possible ways of overcoming drug resistance it is important to understand the mechanisms that are responsible. To date a number of mechanisms that cause resistance are known, but there are still unidentified mechanisms that are associated with drug resistance. The aim of our work is to use a new method to identify unknown drug resistance mechanisms in leukaemia. Once a mechanism is identified, we will determine its relevance in leukaemia by screening a number of patients that have shown resistance to treatment. If identified as a common mechanism of resistance in leukaemic patients, we will test possible agents able to prevent drug resistance that could be used in conjunction with drug during treatment, and to screen new drugs for susceptibility to resistance mechanisms. Diagnostic tests to detect the presence of the known resistance mechanisms prior to treatment could be used in selection of the most appropriate drug combinations for individual patients. Some of the known drug resistance mechanisms that occur in leukaemia are also operative in other forms of cancer and the project is of general relevance to cancer chemotherapy.Read moreRead less
MINIMAL RESIDUAL DISEASE IN ACUTE LYMPHOBLASTIC LEUKAEMIA
Funder
National Health and Medical Research Council
Funding Amount
$455,204.00
Summary
This project will study the extremely small numbers of leukaemic cells which are found in patients who are apparently healthy, but which sometimes lead to relapse. Very sensitive methods for measuring and studying low levels of leukaemic cells will be developed and used. To develop new better treatments in the long term, we will study why current treatment sometimes fails to eradicate the leukaemia, leading to patients relapsing. Clinicians currently need to obtain samples of bone marrow to asse ....This project will study the extremely small numbers of leukaemic cells which are found in patients who are apparently healthy, but which sometimes lead to relapse. Very sensitive methods for measuring and studying low levels of leukaemic cells will be developed and used. To develop new better treatments in the long term, we will study why current treatment sometimes fails to eradicate the leukaemia, leading to patients relapsing. Clinicians currently need to obtain samples of bone marrow to assess leukaemia, and the research will show whether this needs to be continued, or whether, with sensitive tests, samples of blood can be used instead. The study will involve collaboration with clinicians throughout Australia and overseas.Read moreRead less
Genetic Analysis Of Drug Resistance In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Treatment for childhood leukaemia fails in approximately 25% of children owing to resistance to the drugs being used. Our recent evidence suggests that only a few rare leukaemic cells are initially resistant at the commencement of treatment. This project aims to isolate these rare cells and to look for genetic changes in them which might account for their resistance. Hopefully an understanding of the genetic basis for drug resistance will lead to better means of overcoming it.
Drug-induced Immune Thrombocytopenia: Understanding The Disease Mechanisms Is The Key To Better Treatment
Funder
National Health and Medical Research Council
Funding Amount
$509,550.00
Summary
Many very commonly used medications cause an allergic reaction in a small number of patients that receive them. The allergic reaction results in platelets being destroyed and puts the patients at risk of bleeding. The patient recovers slowly if the drug is stopped but there is no other treatment and no way to reverse the effect quickly if the patient starts to bleed. This project will try to understand the mechanism of the condition and test a potential treatment.
Development And Assessment Of Novel Assays To Predict Response To Second-line TKI Therapy In Imatinib-resistant CML
Funder
National Health and Medical Research Council
Funding Amount
$491,308.00
Summary
Patients with chronic myeloid leukaemia (CML) respond well to imatinib, the first small molecule developed to block the kinase activity of the causative oncogene in CML, BCR-ABL. However some patients develop resistance. Several new kinase inhibitors are now available that are effective in some patients with imatinib resistance. We plan to develop biological and molecular assays to predict if a CML patient will respond to a specific second-line kinase inhibitor to optimise second-line therapy.
Modern chemotherapies are designed to exert maximal effect on tumour cells while having minimal side-effects on normal cells. Remarkable advances in our understanding of the molecular biology of cancer has provided possible avenues for more successful targeted cancer treatments. Several crucial interactions between cancer-specific proteins called oncoproteins , occur largely in tumour cells and thus provide ideal targets for intervention. The proposed project is to develop a model system for a t ....Modern chemotherapies are designed to exert maximal effect on tumour cells while having minimal side-effects on normal cells. Remarkable advances in our understanding of the molecular biology of cancer has provided possible avenues for more successful targeted cancer treatments. Several crucial interactions between cancer-specific proteins called oncoproteins , occur largely in tumour cells and thus provide ideal targets for intervention. The proposed project is to develop a model system for a target specific therapy of leukaemia cells by blocking the interactions between oncoproteins. Moreover, the ability to isolate specific blockers of particular protein-protein interactions provides an opportunity to unravel complex genetic pathways in mammalian systems, which are relatively intractable by other analyses. The dissection of pathways using specific blockers may also provide a useful avenue for identifying new drug targets. We have chosen to target particular interactions involving one known oncoprotein in the search for specific inhibitors. A genetic selection will be used to identify random, constrained peptide sequences which are capable of blocking these interactions and which do not interfere with other interactions involving the oncoprotein. This technique allows one to select for or against specific blockers of known interactions from a library containing millions of candidate drug leads in baker's yeast cells. This procedure will be most suitable for high through-put drug screening projects. The validity of this approach to the identification of new peptide drug leads will be finally established in vivo using transgenic models of oncoprotein-dependent cancer in mice.Read moreRead less