Translational Research Program To Advance Clinical Outcomes In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$418,192.00
Summary
Five-year survival in acute myeloid leukaemia (AML) is only 27%, placing it amongst the worst-ranked cancers for clinical outcome. Improved patient outcomes will be achieved through implementation of a Translational Research Program to support novel agent drug testing, early-phase and randomised clinical trials and a national clinical registry to audit outcomes. New insights into leukaemic stem cell function and mechanisms of drug resistance will inform the design of future clinical trials.
Overcoming The Differentiation Block In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$811,669.00
Summary
Acute myeloid leukaemia (AML) is an aggressive leukaemia with poor overall survival. About 50% of AML cases have genetic mutations that disable PU.1, which in turn alters the expression of many other genes that cause leukaemia. We have developed new AML models allowing reversible inhibition of PU.1, and have shown that re-engaging PU.1 function causes AML regression. This project aims to understand PU.1 functions in AML and identify rational drug targets for treatment-resistant disease.
Understanding The Multistep Pathogenesis Of T-cell Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$701,992.00
Summary
Lmo2 is a transcription factor whose overexpression is a common cause of T-cell leukaemia. This project seeks to identify downstream targets of Lmo2 that cause T-cell leukemia. In addition, the origins and effects of secondary mutations that collaborate with Lmo2 in causing T-cell leukaemia will be determined. This will improve our understanding of how T-cell leukaemia develops and provide new molecular targets for therapy.
Investigating The Molecular Basis For Drug Resistance And Disease Relapse In Myelodysplastic Syndromes
Funder
National Health and Medical Research Council
Funding Amount
$722,557.00
Summary
Myelodysplastic Syndromes (MDS) are a group of blood stem cell disorders that result in low blood counts and leukemia especially in the elderly. Azacitidine (AZA) is a drug that improves blood counts and delays progression to leukemia and is the treatment of choice. However, only half the patients treated with AZA ever respond and half of the responders relapse within a year. We will describe the origins of MDS and the basis for drug response, resistance and disease relapse.
Targeting Epigenetic Enzymes In Core Binding Factor AML
Funder
National Health and Medical Research Council
Funding Amount
$542,273.00
Summary
Acute myeloid leukemia (AML) is a devastating disease and there are ~900 new cases diagnosed annually in Australia. A subset of AML, called core binding factor (CBF) AML is more responsive to conventional chemotherapies than other AMLs however patients still relapse indicating a need for new therapies. We will use preclinical models of CBF AML to identify the proteins and pathways that these leukemias are “addicted” to in order to develop new treatment options for these patients.
Combinatorial Therapeutics In High-risk Infant Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$340,891.00
Summary
Modern therapies for children with leukaemia are curative in more than 90%. In contrast, survival for infants less than one year of age at the time of diagnosis is less than 50%. Better therapies are desperately needed. From laboratory testing we have discovered effective novel cancer drugs, which are not currently used for treatment of babies with leukaemia. We will evaluate novel drug combinations and test them in model systems, such that they can be fast-tracked to the clinic.
GADD45A Promoter Methylation And Poor Prognosis In AML:mechanism And Clinical Significance
Funder
National Health and Medical Research Council
Funding Amount
$706,280.00
Summary
DNA methylation associated with the GADD45A gene defines an AML patient group with poor overall survival and limited treatment options. We will investigate the significance of this modification for the response of AML cells to chemotherapy and dissect the mechanism associated with this event. To translate these findings into the clinic we will test whether these patients are responsive to new agents targeting DNA methylation, and investigate survival of patients in a large independent cohort
Transposon Mutagenesis For Discovery Of Disease Causing Genes And Their Cooperative Interactions In Acute Myeloid Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$659,302.00
Summary
The emergence of cancer is caused by multiple mutations in normal cells. Recent progress has allowed the detection of virtually all mutations in a cancer genome. Although this has been enormous progress, it has become increasingly evident that only rare mutations are responsible for sustained tumour growth and treatment failure, while the majority of mutations are without effect. Our research will assist identification of the genetic changes essential to leukemia development, which will help dev ....The emergence of cancer is caused by multiple mutations in normal cells. Recent progress has allowed the detection of virtually all mutations in a cancer genome. Although this has been enormous progress, it has become increasingly evident that only rare mutations are responsible for sustained tumour growth and treatment failure, while the majority of mutations are without effect. Our research will assist identification of the genetic changes essential to leukemia development, which will help develop new cancer therapies.Read moreRead less
Targeting Sphingosine Kinase 1 To Sensitise Acute Myeloid Leukaemia To BH3 Mimetic Therapy
Funder
National Health and Medical Research Council
Funding Amount
$670,005.00
Summary
Acute Myeloid Leukaemia (AML) patients are currently treated with chemotherapeutics and despite their success at achieving disease remission these responses are often short lived, resulting in relapse and death. We have identified sphingosine kinase 1 as a new drug target in AML. This proposal aims to examine the role of targeting sphingosine kinase 1 in combination with new targeted therapies in patient samples and preclinical mouse models of AML.
Epigenetic Regulation Of Self-renewal Signalling Pathway In Leukemic Stem Cell Formation
Funder
National Health and Medical Research Council
Funding Amount
$885,476.00
Summary
Acute myeloid leukaemia (AML) is a fatal form of blood cancer. The survival of patients with AML remains poor and this is due to the return of disease after chemotherapy (relapse). Leukemic stem cells (LSCs) are the major cause of relapse and we study how LSCs are regulated. This will provide valuable input into the development of novel therapeutic strategies to target therapy-resistant LSCs and improve AML outcome.