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
We recently discovered a new way to treat melanoma by inhibiting a protein called MDM4 that is important in promoting tumor growth in ~2/3 of melanomas. In this proposal, we will extend this work to see if anti-MDM4 therapy is effective in laboratory models that are more relevant to patients and in combination with other melanoma therapies. We will also explore additional ways of inhibiting MDM4 that may make anti-MDM4 therapy even more potent.
Apoptosis And Stem/Progenitor Cells In The Development And Treatment Of Cancer
Funder
National Health and Medical Research Council
Funding Amount
$21,809,604.00
Summary
To improve cancer therapy, we are studying two cancer hallmarks. The first is excessive cell survival. To combat this, we are developing drugs with commercial partners that directly activate the cell's death machinery. The second hallmark is inexorable proliferation, akin to that of stem cells, which can generate entire tissues, as we showed for the breast. ‘Rogue’ stem-like cells may initiate certain cancers. We hope to advance cancer therapy by identifying such cells and drugs that kill them.
Development Of Novel And Selective Anticancer Drugs Derived From Cysteine.
Funder
National Health and Medical Research Council
Funding Amount
$264,250.00
Summary
In the next few years cancer is projected to become the leading cause of death in industrialised countries. Cancer chemotherapy currently relies on destruction of tumours by toxic drugs that indiscriminately kill all cell types, resulting in side effects that limit treatment. In the 21st century new cancer drugs will more effectively destroy malignant tumour cells without damaging normal cells. The R and D herein will value-add to our discovery of a new class of potent and orally active anti-tum ....In the next few years cancer is projected to become the leading cause of death in industrialised countries. Cancer chemotherapy currently relies on destruction of tumours by toxic drugs that indiscriminately kill all cell types, resulting in side effects that limit treatment. In the 21st century new cancer drugs will more effectively destroy malignant tumour cells without damaging normal cells. The R and D herein will value-add to our discovery of a new class of potent and orally active anti-tumour drugs that possess unusually high selectivity in acting on cancer cells without killing normal human cells. Our current proof of concept will be turned into a drug development candidate that will improve our negotiating position with commercial partners.Read moreRead less
The Effect Of Histone Deacetylase Inhibitors On The Bone Environment In Multiple Myeloma
Funder
National Health and Medical Research Council
Funding Amount
$356,899.00
Summary
Multiple myeloma (MM) is an incurable hematological malignancy with 1,400 people diagnosed each year. Severe bone loss occurs in up to 90% of these patientssignificantly impacting on quality of life resulting in severe bone pain and bone lesions that fail to heal. This project proposes that a novel histone deacetylase inhibitor could provide an appropriate therapeutic strategy that inhibits tumor growth and prevents bone loss whilst also promoting bone repair.
Osteosarcoma is the most common tumour of bone. Recent success in targeting immune checkpoint blockers such as Programmed death-1 (PD-1) in genomically complex tumours suggests that osteosarcomas may be amenable to such strategies. We will characterise the role of the PD-1 pathway in osteosarcoma development and growth. Using preclinical mouse models we will investigate the biology of the PD-1 pathway and study its potential as a therapeutic target in advanced and resectable osteosarcoma.
Isoform Selective PI3 Kinase Inhibitors For Cancer, Thrombosis And Inflammatory Disease
Funder
National Health and Medical Research Council
Funding Amount
$474,473.00
Summary
Inhibitors of the PI3 kinase family of enzymes have potential as therapeutics in diseases such as cancer, thrombosis and inflammatory disease. In this project the investigators will develop a new class of PI3 kinase inhibitors they have discovered, optimizing their pharmaceutical properties and evaluating them in models of disease. The aim is to develop a candidate for human clinical studies.
Actin filaments are part of a dynamic network of protein fibres inside each cell and play a role in cell shape, movement and division. Cancer cells hijack specific types of actin filaments to spread throughout the body. Our aim is to find out how protein machines assemble these filaments from actin and different binding proteins that give each filament its specific function. This insight will allow us to improve drugs that inhibit filaments associated with cancer.