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.
Developing Novel Molecules To Down-Regulate Src Family Tyrosine Kinases
Funder
National Health and Medical Research Council
Funding Amount
$201,261.00
Summary
Leukaemia and cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of the common biochemical characteristics of cancer-leukaemia cells is augmented activity levels of enzymes called tyrosine kinases. A major group of tyrosine kinase involved in several cancer-leukaemia types is called the Src family of tyrosine kinases. One member of this family called Lyn has been our focus of study for several years, investigating the signalling ....Leukaemia and cancer cells have altered biochemical properties resulting in their high rate of growth compared to normal cells. One of the common biochemical characteristics of cancer-leukaemia cells is augmented activity levels of enzymes called tyrosine kinases. A major group of tyrosine kinase involved in several cancer-leukaemia types is called the Src family of tyrosine kinases. One member of this family called Lyn has been our focus of study for several years, investigating the signalling pathways that it is involved in. This molecule has also been implicated in several specific leukaemia (Chronic Myeloid Leukaemia and Acute Myeloid Leukaemia) as well as cancer (Prostate, Colon, Breast) in recent years. We have identified a novel mechanism of down-regulation of this enzyme mediated by an adapter molecule called Cbp, which recruits the Lyn inactivating molecules Csk-Ctk as well as SOCS-1; together they inhibit the activity of Lyn and degrade the enzyme. Using our knowledge of the essential interaction elements of Cbp we will design and test various mini-Cbp molecules for their ability to inactivate and degrade Lyn in leukemic and cancer cells. These molecules may allow us to develop novel therapeutics capable of inactivating-degrading specific tyrosine kinases in cancer and leukaemia.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
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
A Novel Cytokine-receptor Survival Axis In Chronic Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$424,731.00
Summary
Cancer cells grow and survive in an unrestrained manner. Current therapies target cancer growth, however they permit the long-term survival of some cancer cells and increase the possibility of drug resistance and disease relapse. We have identified a new molecular switch that is constitutively activated (unregulated) in leukemia. Targeting specific components of this unregulated cell survival may provide new and improved approaches for the development of therapeutics in the treatment of leukemia
New Compounds For Tailored Therapy Against MLL-rearranged Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$326,401.00
Summary
Some of the worst leukaemia survival rates are found in children and adults whose leukaemias display abnormalities of the MLL gene and alternative therapies are therefore urgently required for these patients. The aim of this project is to develop new compounds that specifically inhibit this abnormal gene and in turn inhibit the growth of these cells in the patient. In this way we hope to provide new and more effective therapies for patients affected with this aggressive type of leukaemia.
In Australia seventeen persons are diagnosed with leukemia or a related blood disorder each day. An understanding of the way the body controls blood cell production has widespread relevance to diseases like leukemia and the way that they are treated. The burden of this disease on the Australian health budget will continue to increase dramatically as our population ages in coming years. Moreover, an understanding of blood cell production has wider relevance to similar control mechanisms in other ....In Australia seventeen persons are diagnosed with leukemia or a related blood disorder each day. An understanding of the way the body controls blood cell production has widespread relevance to diseases like leukemia and the way that they are treated. The burden of this disease on the Australian health budget will continue to increase dramatically as our population ages in coming years. Moreover, an understanding of blood cell production has wider relevance to similar control mechanisms in other organs, as nature reuses its best inventions. Australia has had an enviable international record in discoveries related to factors controlling blood cells and we wish to continue that tradition by examining an exciting new development involving microRNAs. These molecules are found in all normal cells but they have been ignored until recently. Although the field is in its infancy, we now know that these microRNAs are likely to be involved in many cellular processes. In this project we will study the importance of this new class of regulatory molecule in order to discover previously-hidden functions in normal blood cells and their malignant counterparts (leukemias) in humans. The team comprises two laboratories which have collaborated for many years and already a number of exciting molecular methods have been developed. Ultimately this project may lead to novel treatments involving gene therapy, bone marrow transplantation and blood hormones.Read moreRead less
The Role Of Hox Genes In Myeloid Cell Development And Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$591,286.00
Summary
The transformation of normal white blood cells into leukaemic cells occurs as a result of changes to the genes of those cells. These changes are often characteristic of particular cancers and carry diagnostic and prognostic significance. This work will determine how critical some of the typical genetic changes of leukaemia are to the occurrence and persistence of cancer. Importantly, we will determine whether targeting these changes can provide new and effective approaches to treatment.
Klf5 Function In Normal And Leukaemic Haemopoiesis
Funder
National Health and Medical Research Council
Funding Amount
$609,924.00
Summary
Acute Myeloid Leukaemia (AML) is a devastating disease that affects both children and adults. New treatments that target particular genetic abnormalities are urgently needed. We have identified KLF5 as a gene that may control blood cell maturation. In AML patient samples we have found alterations of the KLF5 gene that may suppress its activity and contribute to the formation of leukaemia. These leukaemias may be good candidates for treatment with new drugs called methyltransferase inhibitors.
Acute myeloid leukaemia (AML) is a major health problem with only about one third of patients being cured. In addition therapies have changed little over the last 20 years. However there is optimism that with greater knowledge of the biochemical changes in AML that are caused by genetic mutations, more effective treatments will be developed. This project therefore aims to increase understanding of the biochemical interplay between two proteins called c-Cbl and Flt3 that are altered in AML.