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
A Randomized Trial Of Idarubicin Dose Escalation In Consolidation Therapy For Adult Acute Myeloid Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$425,000.00
Summary
This project is a clinical trial to test the value of giving a higher than usual dose of one of the most important anti-cancer drugs, called idarubicin, in the initial treatment of adults with newly diagnosed acute myeloid leukemia (AML). This disease is the most serious form of leukemia in adults, and is usually treated with strong anti-cancer drugs, including idarubicin. Research in Australia and overseas has shown that increasing the doses of the other major drug (called cytarabine) used to t ....This project is a clinical trial to test the value of giving a higher than usual dose of one of the most important anti-cancer drugs, called idarubicin, in the initial treatment of adults with newly diagnosed acute myeloid leukemia (AML). This disease is the most serious form of leukemia in adults, and is usually treated with strong anti-cancer drugs, including idarubicin. Research in Australia and overseas has shown that increasing the doses of the other major drug (called cytarabine) used to treat AML in adults results in a doubling of the number of people cured of this disease, given that they have achieved a remission. This project will examine whether there is a similar benefit of increasing the idarubicin dose beyond that which has been conventionally used up to date. People who have AML diagnosed at one of the Australian hospitals participating in this study will receive initial treatment with an established drug combination. Those patients achieving a good response to the first treatment will then be randomly allocated to receive 2 further courses of treatment, one with a conventional dose of idarubicin, and the other with double the idarubicin dose. All patients will then be assesed for side effects of the treatment, and followed for at least 3 years for any signs of recurrence of their leukemia.Read moreRead less
Biomarkers And EGFR Inhibitor Treatment Of Lung Cancer
Funder
National Health and Medical Research Council
Funding Amount
$286,328.00
Summary
Non-Small Cell Lung Cancer (NSCLC) remains the most frequent cause of cancer death in the Australian population. This laboratory research will involve researchers across a number of centres in Australia. The research is focused on the effects of a new targeted cancer drug called cetuximab. The Epidermal Growth Factor Receptor (EGFR) pathway is an important cause of NSCLC in many patients, and this is blocked by cetuximab. The advent of new targeted cancer therapies, which block specific cancer p ....Non-Small Cell Lung Cancer (NSCLC) remains the most frequent cause of cancer death in the Australian population. This laboratory research will involve researchers across a number of centres in Australia. The research is focused on the effects of a new targeted cancer drug called cetuximab. The Epidermal Growth Factor Receptor (EGFR) pathway is an important cause of NSCLC in many patients, and this is blocked by cetuximab. The advent of new targeted cancer therapies, which block specific cancer pathways in the cell, has highlighted the need for detailed knowledge about how these therapies work at the molecular level, so that we can make best use of them. The laboratory studies will be on tissues taken from patients with NSCLC who are receiving chemotherapy then going on to surgery to have the cancers removed. Tumour samples will be taken prior to treatment, and then the surgical resection will also be analysed. Sequential blood samples will also be taken. Prior to surgery, patients will receive a 9 week course of chemotherapy with cisplatin and docetaxel to shrink the cancer. In addition, some patients will be randomised to receive cetuximab along with chemotherapy. In the laboratory, we will investigate whether various measures of activation of the EGFR pathway in the cancer and in blood predict for response to cetuximab. We will also investigate how the changes in tumour with cetuximab treatment differ from tumours not treated with the drug. We will be examining the genes and proteins of EGFR and those of a number of related pathways. a number of related receptor, along with From this we will attempt to understand which patients benefit most from the drug and also in what specific ways the cancer cells are affected by the treatment.Read moreRead less
Molecular Targeting To Telomerase And Cancer Cell Immortality By A Novel Inhibitor
Funder
National Health and Medical Research Council
Funding Amount
$430,812.00
Summary
Infinite growth of cancer cells is a hallmark of cancer. Telomerase is required for cancer cell immortality. Inhibition of telomerase may thus offer an opportunity to stop cancer cells. We have identified an inhibitor of telomerase. This project will study the mechanisms of action of the novel inhibitor, investigating how to control cancer cell immortality as a baseline for more applied anti-cancer therapeutic studies.
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
Investigating Tumour Maintenance Using Regulated RNA Interference
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
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 validate potential drug targets in cancer by using RNAi to inhibit specific genes in established mouse tumours. A further aim is to use RNAi to mimic human cancer gene mutations in mouse cancer models, to discover novel tumour suppressor genes.