Investigating The Role Of Mutant P53 And MCL-1 In The Sustained Growth Of MYC Lymphomas And Strategies For Targeted Therapy
Funder
National Health and Medical Research Council
Funding Amount
$616,940.00
Summary
A large number of human cancers have abnormal expression of a protein called MYC, leading to rapid growth. We found that when another protein called MCL-1 was inactivated, the lymphomas regressed. Importantly, mutations in the tumour suppressor gene called p53 are frequently found in cancer cells and we noticed that this could reduce the dependency on MCL-1. We aim to investigate this further in this grant proposal, in part using a novel drug that targets MCL-1.
IL21, B-cell Proliferation And The Mechanism Of Memory Formation
Funder
National Health and Medical Research Council
Funding Amount
$981,896.00
Summary
Our immune system can ‘remember’ old infections, which is why we do not suffer from the same pathogen multiple times and why vaccines work. Much of this protection is due to memory B-cells, of which there are different kinds. We think the different memory B-cell subsets have different functions and understanding how they are made and how this is controlled will help us improve responses to critical infections – HIV, Flu – and in critical patient groups – aged people and transplant recipients.
LRH-1 is a protein that is inappropriately present in cancers of the breast and other tissues. It causes cancer cells to divide and multiply, and therefore it is important to block its activity. There are, however, no treatments available that block LRH-1. This proposal brings together a team of researchers with broad experience. We will use high throughput technologies to identify and characterize novel LRH-1 inhibitors, and demonstrate their efficacy in reducing the growth of cancer cells.
An exciting area of drug discovery involves targeting Hippo pathway proteins, particularly one called YAP, which were discovered by members of our research team and which are highly active in some cancer cells, making them grow and spread. We will test whether YAP is a potential drug target to prevent or treat melanoma, a deadly type of cancer that usually arises in the skin but also internal organs and the eye. If so, we would fast-track these drugs for testing in patients via clinical trials.
Deciphering The Function Of Caspase-2 In DNA Damage Response And Tumour Suppression
Funder
National Health and Medical Research Council
Funding Amount
$808,007.00
Summary
Aberrant cell death and DNA damage response (DDR) are hallmarks of tumourigenesis. Recently we have discovered that an enzyme, caspase-2, previously implicated in cell death execution, also works in DDR and acts as a tumour suppressor. We now wish to validate these finding in preclinical models of cancer and understand precisely how caspase-2 safeguards against cancer development. These studies will help better understand tumourigenesis and may lead to the discovery of new drug targets.
Cell Cycle Tracking Of B Cell Differentiation And Mutation
Funder
National Health and Medical Research Council
Funding Amount
$719,666.00
Summary
Antibody-mediated immunity to infectious diseases requires the proliferation of infection-specific antibody-producing B cells. The fate of responding B cells is linked to this proliferation according to a poorly understood division-based “map”. This project will track B cell fates in vivo using advanced imaging techniques. We will define differences between B cells from young versus old individuals that may explain why the effectiveness of the immune system declines with age.
Defining The Role Of Microphthalmia-associated Transcription Factor (MITF) In Melanoma Heterogeneity By Real-time Cell Cycle Imaging
Funder
National Health and Medical Research Council
Funding Amount
$613,705.00
Summary
Metastatic melanoma is highly therapy-resistant. Modern targeted therapy is promising but suffers from rapid onset of drug resistance. Tumours consist of zones of fast growing cells next to zones of dormant cells. This tumour heterogeneity is one of the reasons for cancer drug resistance, as cells in different growth states respond differently to drugs. By understanding the causes of tumour heterogeneity we will set the basis for innovative clinical approaches against this devastating disease.
EAR2: A Novel Driver Of Breast Cancer Proliferation
Funder
National Health and Medical Research Council
Funding Amount
$725,476.00
Summary
Drugs that block oestrogen are effective breast cancer treatments, but many patients are resistant to their effects. This research addresses a protein known as EAR2, that is elevated in breast cancer tissue compared to normal breast. We hypothesise that EAR2 drives breast cancer cell proliferation, and will test this using cell lines and mouse models. We will validate EAR2 as a new therapeutic target, benefitting patients underserved by current hormone therapies.
Role Of The Drug Metabolising Enzyme Arylamine N-acetyltransferase 1 In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$600,196.00
Summary
The current project will identify the molecular mechanism(s) that underpins the significant changes in phenotype seen in a range of human cancer cells. The expected outcomes will be to demonstrate that NAT1 is critical for the clearance of pABG in cancer cells. The results will be important in the context of understanding this family of intracellular enzymes and will change the current thinking on the function of the arylamine N-acetyltransferase in normal and cancer cells.
Characterisation Of Two New Kinases In The Hippo Tumour Suppressor Pathway
Funder
National Health and Medical Research Council
Funding Amount
$550,602.00
Summary
The Hippo pathway is a key regulator of tissue growth. It was first discovered in vinegar flies and plays a similar role in mammals. We aim to define the mechanism by which the Gish and Fray kinases control tissue growth by regulating the Hippo pathway. These studies will be performed in flies and mammalian cell culture. Our studies will shed light on how tissue growth is controlled, and have the potential to inform the way that we treat human cancers and tissue growth disorders.