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.
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
Toward Effective Targeted Therapies For Acute Myeloid Leukaemia (AML)
Funder
National Health and Medical Research Council
Funding Amount
$551,345.00
Summary
Standard chemotherapy for acute myeloid leukaemia (AML) is highly toxic, and has not changed in over 40 years. We will conduct a world-first clinical trial incorporating ABT-199 (Venetoclax) to target BCL2 into the standard-of-care treatment for AML. A second initiative will explore the potential for small molecule inhibitors to simultaneously target both BCL2 and its related partner MCL1, to create a “chemotherapy-free” regimen for AML. These studies promise to herald a new era in AML therapy.
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
The Mutagenic Influence Of 5-methylcytosine And Its Relevance For Cancer Treatment
Funder
National Health and Medical Research Council
Funding Amount
$844,462.00
Summary
Over time our cells accumulate damage to their DNA, which introduces mistakes in the genetic code. These mistakes can alter genes that regulate cell growth and survival and, in this way, they begin the process of turning a normal cell into a cancer. This research is investigating the cellular repair mechanisms that safeguard against DNA damage. Manipulating these repair mechanisms may offer a new way to treat cancer, by selectively inducing DNA damage within cancer cells.
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.
Understanding Response And Resistance To Inhibition Of Mutant Isocitrate Dehydrogenase In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$581,979.00
Summary
Acute myeloid leukaemia (AML) is an aggressive cancer of white blood cells and development of novel treatment options is urgently needed. Mutations in enzymes known as isocitrate dehydrogenase (IDH) -1 and -2 are amongst the most common in AML and recent studies strongly suggest that mutant IDH proteins are attractive drug targets. In this proposal we will use advanced genetic tools to comprehensively analyse the role of IDH dysfunction in leukaemia initiation, development and progression.
Targeting Leukaemia Stem Cells Through Inhibition Of Telomerase
Funder
National Health and Medical Research Council
Funding Amount
$651,979.00
Summary
Acute myeloid leukaemia (AML) is a type of very aggressive blood cancer that kills up to 1000 Australians every year. We use chemotherapy to treat AML, however, most patients are not cured by chemotherapy alone and the disease eventually comes back (relapses). We are looking at a new type of treatment for patients with AML that targets the genetic material (DNA) within the leukaemia cells. Our work has shown that this new type of treatment may prevent relapse after chemotherapy.
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.