Synthetic Analogues Of The Actinomycin, Quinamycin And Nogalamycin Groups Of Antitumour Antibiotics
Funder
National Health and Medical Research Council
Funding Amount
$376,433.00
Summary
The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar ....The principal difficulty in the treatment of the common solid tumours that cause the majority of cancer deaths is the problem of drug resistance. For example, many patients with cancer of the lung, breast or colon respond well to drug treatment with their tumours initially regressing, only to return later in an aggressive drug-resistant form. In this event, the inevitable outcome is that the tumour grows through drug treatment and the patient eventually succumbs and dies. This is also a familiar scenario in the treatment of adults with leakaemias and non-Hodgkins lymphomas. The underlying cause of drug resistance is the genetic instability of cancer cells which results in tumours that are heterogeneous, making it almost inevitable that a cancer cell will arise that is resistant to treatment. There are many mechanisms of resistance, some of which are peculiar to particular drug types, some are permeability barriers and some involve genetic deregulation of the biochemistry of cell death. One way of subverting resistance is by the use of drugs whose mechanism of action is novel so that the tumour is challenged to devise a new defense. Here, we are attempting to develop synthetic analogues of a class of naturally- occurring antitumour antibiotic whose mechanism of action is unusual but which has not been exploited by medicinal chemists because of the difficulty of the chemistry involved. These antibiotics work by binding to DNA and inhibiting the first step in the process whereby genes are turned into proteins. We have designed compounds that are chemically accessible that our preliminary work suggests mimic the DNA-binding and biological properties of the natural antibiotics. The proposed work will enable us to evaluate whether this new class of agent has experimental antitumour activity, particularly amongst drug-resistant tumours.Read moreRead less
Improving Cancer Therapy: Nanoparticle Delivery Of SiRNA To Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$610,499.00
Summary
Lung cancer accounts for 8000 diagnosis and 1000 deaths in Australia each year. We are using cutting edge nanotechnology and coupling this with potent gene silencing to target solid tumours of the lung. If successful, this approach could increase survival of patients with this difficult to treat malignancy and may prove valuable in the treatment of other lung tumours.
Development Of A Novel Therapy For The Treatment Of Epidermal Squamous Cell Carcinoma
Funder
National Health and Medical Research Council
Funding Amount
$432,750.00
Summary
Squamous cell carcinomas (SCC) are the most common life-threatening form of skin cancer in Australia. SCCs commonly arise in areas of the body that have been exposed to excessive amounts of UV irradiation. The cells of the skin from which SCCs are derived are called keratinocytes. UV irradiation causes lesions within these cells such that their growth and maturation are disrupted leading to deregulated growth and maturation and hence tumour formation. We have previously identified a protein, E2F ....Squamous cell carcinomas (SCC) are the most common life-threatening form of skin cancer in Australia. SCCs commonly arise in areas of the body that have been exposed to excessive amounts of UV irradiation. The cells of the skin from which SCCs are derived are called keratinocytes. UV irradiation causes lesions within these cells such that their growth and maturation are disrupted leading to deregulated growth and maturation and hence tumour formation. We have previously identified a protein, E2F, that is central to this process and whose inhibition leads to decreased cancer cell growth. During the course of these studies we noted that the deregulation of E2F could also lead to the disruption of keratinocyte maturation. This led us to propose that the inhibition of E2F in SCCs may result in both decreased cancer cell growth as well as the reinstatement of a normal maturation process. this would make E2F inhibitors a very attractive therapeutic for treating SCC. In the present study we aim to explore the ability and the mechanism by which E2F modulates keratinocyte proliferation and maturation. This will be done in vitro as well as in animal models of SCC. These studies will be required in order to take the E2F inhibitors into clinical trials.Read moreRead less
Targeting Eph Receptors As Anti-cancer Therapy In Malignant Glioma.
Funder
National Health and Medical Research Council
Funding Amount
$403,639.00
Summary
Malignant gliomas are the commonest form of brain cancer and are characterised by a high degree of morbidity and mortality. Present treatment involves surgery and adjuvant chemoradiotherapy but despite best care the outlook for patients with this disease is poor. The increasing understanding of the biology of glioma offers the prospect of improved therapies. This proposal seeks to investigate a therapy target in this disease in animal models of human malignant glioma.
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
Epimutations As Germ-line Defects In Hereditary Cancer Syndromes
Funder
National Health and Medical Research Council
Funding Amount
$385,925.00
Summary
Traditionally familial cancers were thought to be caused and inherited by spelling mistakes within the genetic code of cancer prevention genes. Our group has found that a 'chemical coat' around the MLH1 gene, causing it to be switched off, can also be inherited in some cases of bowel cancer, without any mistakes within the gene's code. We will determine if this 'coat' causes other types of cancer and if this runs in families. We also hope to find out how the coat is formed and may be reversed.