Breast cancer remains the major form of cancer diagnosed in women, and is still the leading cause of cancer death. There remains a pressing need to find better ways to treat this disease. Increasingly, cancer treatments will make use of a growing knowledge of the factors that normally regulate cell growth, and will apply this knowledge to make cancer cells more sensitive to existing anticancer treatments. We are proposing here to study the hormone calcitonin as a novel regulator of cancer cell g ....Breast cancer remains the major form of cancer diagnosed in women, and is still the leading cause of cancer death. There remains a pressing need to find better ways to treat this disease. Increasingly, cancer treatments will make use of a growing knowledge of the factors that normally regulate cell growth, and will apply this knowledge to make cancer cells more sensitive to existing anticancer treatments. We are proposing here to study the hormone calcitonin as a novel regulator of cancer cell growth. Calcitonin is better known as a hormone that inhibits bone loss, by acting on bone resorbing cells called osteoclasts. However, our present proposal is based on our recent finding that the receptor for calcitonin is for some reason also found in many breast cancers. Moreover, we have shown that calcitonin can potently inhibit the growth of cells that have the calcitonin receptor on their surface. We plan to extend these findings in 4 ways: 1 We will make use of a large bank of breast cancer samples at the Royal Adelaide Hospital to determine whether the presence of the calcitonin receptor in breast cancers is related to other features of the tumours, such as their propensity to spread to other organs. 2 We will investigate the mechanisms by which calcitonin slows the growth of cells. 3 We have unique access to new calcitonin-like molecules, called calcitonin mimetics, which we will investigate for the ability to inhibit cell growth. These molecules are much cheaper and probably easier to administer than calcitonin itself. 4 We will investigate whether treatment of cells with calcitonin makes them more sensitive to other anticancer treatments. We hope that success in this project will lead to a more detailed understanding of the way that molecules like calcitonin can regulate cell growth and to new treatment options for cancer.Read moreRead less
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
Development Of DNA Phosphate Crosslinking Agents As Potential Anticancer Drugs
Funder
National Health and Medical Research Council
Funding Amount
$392,545.00
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 leukaemias 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. Alkylating agents are one of the most important classes of anticancer drug. They bind irreversibly to the bases in DNA and weld the two strands of the double helix together. This cross-link is a powerful block to DNA replication and leads to the death of cancer cells by the process of programmed cell death. Cancer cells generally become resistant to alkylating agents by invoking repair mechanisms that remove the drug from the DNA bases, a response which breaks the cross-link and returns the DNA to its normal state. In this project, we are developing a new type of alkylating agent that reacts not with the DNA bases but with the phosphate groups of the DNA backbone. By this means the strands of DNA can again be cross-linked but now the linkage is between parts of the DNA that cancer cells cannot separate. In this way, we hope to be able to devise new drugs that are resistant to the normal mechanisms of DNA repair so that they will be active against drug-resistant tumours.Read moreRead less