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The 3-dimensional Structure Of Anticancer Drug-DNA Complexes Determined By X-ray Crystallography
Funder
National Health and Medical Research Council
Funding Amount
$264,358.00
Summary
Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents ....Our main objective is to discover the molecular details of how cancer drugs interact with DNA and how these interactions differ from those of inactive chemically related compounds. We propose to use X-ray crystallography together with the successful methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of antitumour active drugs to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. These agents act by poisoning the DNA binding enzyme topoisomerase. Crystallographic analysis will give us unequivocal answers at the atomic level as to the exact way in which the drug binds to DNA and how this binding differs between antitumour active and inactive compounds. We believe that a knowledge of the DNA binding mode of a class of intercalating anticancer drugs at the atomic level is valuable in guiding drug design within that class.Read moreRead less
The Structural Basis For The Action Of Anticancer DNA-intercalating Topoisomerase Poisons
Funder
National Health and Medical Research Council
Funding Amount
$459,750.00
Summary
Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs ....Cancer kills one in four people in the Western world and half of those afflicted will die from the disease. If the malignancy is detected early, surgery and radiotherapy will often effect a cure but if the disease is disseminated at presentation then treatment requires chemotherapy. Chemotherapy can be curative for some tumour types but it is generally only palliative for the overwhelming majority of solid cancers. Consequently, there is an urgent need to improve the efficacy of anticancer drugs. Many of these drugs work by binding directly to DNA and poisoning the DNA-manipulating enzyme, topoisomerase. Our objective is to discover the molecular basis of how anticancer drugs act through their interaction with DNA and topoisomerase. We propose to use the successful X-ray crystallography methods we have developed for determining the 3-dimensional structures of the DNA complexes of a class of anti-tumour active drugs, to study the complexes of other clinically or scientifically important DNA intercalating anticancer drugs. Crystallographic analysis provides unequivocal data, at near atomic resolution, of the nature of the molecular interactions which provide specificity and selectivity in drug-DNA complexes. This information will be a valuable guide in the further development of this important class of topoisomerase poisons as anticancer drugs. We will initiate structural studies of ternary complexes between the topoisomerase enzyme, DNA and anticancer drugs. The solution of the X-ray crystal structures of these ternary complexes will allow the design of new antitumour topoisomerase poisons to be put on a completely rational basis.Read moreRead less
Advanced Anti-cancer Activities With Therapeutic Agents That Induce Tumor Cell Apoptosis And Antitumor Immune Responses.
Funder
National Health and Medical Research Council
Funding Amount
$85,701.00
Summary
The aim is to perform pre-clinical studies to identify new therapies for blood cancers. We will utilise three new anti-cancer agents that kill tumor cells and genetically engineered mice that develop cancer. We will determine if these three new agents kill the mouse tumor cells and activate anti-tumor immunity. The combined effect of killing blood cancer cells using new therapeutics, coupled with enhancing the anti-cancer immune response may hold the key to developing new treatments.
Analysis Of The Apoptotic And Therapeutic Effects Of Histone Deacetylase Inhibitors On Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
Multiple myeloma (MM) is an incurable progressive cancer of plasma cells within blood. It is the second most common blood cancer and represents 2% of all cancer-related deaths. Statistics show increasing incidence and decreasing age of onset. The cause and progression of MM is poorly understood and current treatments are frequently followed by relapse. This project will assess exciting new therapies against the survival of MM cells leading to more effective treatments in the future.
Investigating Tumour Biology Using Regulated RNAi In Cells And Mice
Funder
National Health and Medical Research Council
Funding Amount
$305,915.00
Summary
Inhibiting gene expression using the recently discovered process known as RNA interference (RNAi) can be used as an experimental tool to analyse specific genes, in cells and genetically engineered animal models of human disease. I propose to use RNAi to mimic human cancer gene mutations in mouse cancer models, and aim to discover novel tumour suppressor genes. A further aim is to validate potential drug targets in cancer by using RNAi to inhibit specific genes in established mouse tumours.
I am a cancer cell biologist investigating molecular mechanisms of leukaemia cell resistance to chemotherapeutic drugs, and novel strategies for the management of high risk or relapsed disease. For these purposes I have developed orthotopic xenograft mode
Colorectal Cancer - Molecular Basis To Targeted Therapeutics.
Funder
National Health and Medical Research Council
Funding Amount
$19,818,386.00
Summary
Cancer of the colon and rectum is the most common form of cancer in Australia. Over 12,000 people are diagnosed each year with colorectal cancer (CRC) and more than one third of people will die of their disease. CRC is caused by mistakes in production of colon cells. Our research aims to discover new ways to detect CRC, develop smart drugs and nanoparticle delivery systems for destroying all types of CRC cells. We will then test our new anti-cancer drugs in clinical trials with CRC patients.
Genetic And Epigenetic Biomarkers In High Risk Colorectal Cancer: Predicting Risk Of Recurrence
Funder
National Health and Medical Research Council
Funding Amount
$64,631.00
Summary
The main aim of this project is to define the prognostic and predictive significance of specific genetic events in patients with high risk (stage III) colorectal cancer. We attempt to explore the differences between primary tumours from patients with and without recurrence at three years. Data from the project will then be used to define a limited set of biomarkers which will aid in clinical decisions regarding the need for adjuvant chemotherapy after surgery for high risk colorectal cancer.