Development Of Novel EGFR Tyrosine Kinase Inhibitors For The Management Of Glioma, Head And Neck And Other Cancers
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
Abnormalities in EGF-EGFR family signalling pathways have been implicated in many human cancers including glioma, squamous cell carcinome of the head and neck, colon, ovary and prostate, and are associated with poor clinical prognosis, non-responsiveness to chemotherapy, and decreased survival. Inhibitors of these pathways would therefore be useful anti-cancer pharmaceuticals. This proposal outlines experiments aimed at understanding the role of the individual EGFR family members in controlling ....Abnormalities in EGF-EGFR family signalling pathways have been implicated in many human cancers including glioma, squamous cell carcinome of the head and neck, colon, ovary and prostate, and are associated with poor clinical prognosis, non-responsiveness to chemotherapy, and decreased survival. Inhibitors of these pathways would therefore be useful anti-cancer pharmaceuticals. This proposal outlines experiments aimed at understanding the role of the individual EGFR family members in controlling a complex signalling network, and the development of novel small molecule inhibitors of these pathways which are specific for individual EGFR family members and which should prove effective in the management of many forms of cancer. Additionally, the potential synergy of these inhibitors in combination therapy with other anti-cancer drugs and reagents which induce cell death will be investigated. These small molecule pharmaceuticals could easily be produced commercially, and taken into clinical trials, in Australia.Read moreRead less
Contribution Of Tumour And Stroma Derived Cysteine Cathepsins To Breast Cancer Metastasis To Bone
Funder
National Health and Medical Research Council
Funding Amount
$447,094.00
Summary
Breast cancer is a serious clinical problem once the disease spreads to distant tissues such as lung and bone. We have identified a group of genes called the cysteine cathepsin proteases that have increased activity in breast cancers that spread to bone and we have shown this in a mouse model and also in human cancer. We will investigate the contribution of these genes to invasion and test whether inhibiting specific cathepsins can prevent spread of breast cancer to bone in our mouse model .
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
MMP13 is upregulated in cancer cells and in the tissue that forms around the cancer (stroma). A new MMP13-specific inhibitor reduces breast cancer growth in a mouse model, both at the primary site and also in bone. We will determine the role of MMP13 made by the cancer cells and stroma, respectively, extend the inhibitor work, and identify proteins being cleaved by MMP13. Being a late-stage manifestation, bone metastasis may represent an important clinical trial setting for MMP inhibitors.