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.
Potential Anti-tumour Agents: Iron Chelators Of The Pyridoxal Isonicotinoyl Hydrazone Class
Funder
National Health and Medical Research Council
Funding Amount
$472,770.00
Summary
Iron (Fe) is essential for proliferation. Generally, cancer cells have a high Fe requirement due to their rapid rate of proliferation making them very susceptible to iron chelators which deplete cells of Fe. The potential of this therapy has been confirmed by the entrance of the chelator, Triapine (Vion Pharmaceuticals), into clinical trials. Further, a wide variety of studies including clinical trials have shown that the clinically used Fe chelator, desferrioxamine (DFO), can have potent anti-t ....Iron (Fe) is essential for proliferation. Generally, cancer cells have a high Fe requirement due to their rapid rate of proliferation making them very susceptible to iron chelators which deplete cells of Fe. The potential of this therapy has been confirmed by the entrance of the chelator, Triapine (Vion Pharmaceuticals), into clinical trials. Further, a wide variety of studies including clinical trials have shown that the clinically used Fe chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial (Cancer Res 1990;50:4929), a marked decrease in tumour burden was observed while there was no significant side effects, demonstrating an appreciable therapeutic index. However, DFO suffers serious problems, including that it requires long infusions and does not readily permeate cells. Considering this, during the current NHMRC grant, we developed a novel group of chelators that show far greater activity than DFO and Triapine at inhibiting cancer growth in vitro and in vivo (Richardson BLOOD 2004;104:1450). These studies have been published in high quality journals such as BLOOD and Clin Cancer Res (Richardson 1995, 1997, 1999, 2001, 2002, 2004a,b,c) Recently, a potent metastasis suppressor gene, known as differentiation related gene-1 (Drg-1), has been identified. Up-regulation of this molecule plays an important role in inhibiting the growth of primary cancers and their metastatic spread. Importantly, we have recently shown that our new chelators markedly up-regulate the expression of Drg-1 in cancer cells and at the same time markedly and selectively inhibit the growth of these cells (Richardson BLOOD 2004;104:2967). Our hypothesis is the marked increase in Drg-1 expression after treatment with chelators could inhibit cancer cell growth and metastasis. Studies in this NHMRC grant renewal will lead to the development of new therapies and a greater understanding of cancer metastasis and biology.Read moreRead less
Iron is essential for the growth of all cells. Generally, cancer cells have a high iron requirement due to their rapid rate of proliferation. This makes them susceptible to the action of drugs called iron chelators that deplete cell iron. A wide variety of studies, including clinical trials in leukemia and neuroblastoma patients, have shown that the clinically used chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial, a marked decrease in ....Iron is essential for the growth of all cells. Generally, cancer cells have a high iron requirement due to their rapid rate of proliferation. This makes them susceptible to the action of drugs called iron chelators that deplete cell iron. A wide variety of studies, including clinical trials in leukemia and neuroblastoma patients, have shown that the clinically used chelator, desferrioxamine (DFO), can have potent anti-tumour activity. Indeed, in an important clinical trial, a marked decrease in tumour burden was observed while there were no significant side effects, demonstrating an appreciable therapeutic index. However, DFO suffers from serious problems, including that it requires long infusions and does not readily penetrate cells. Further, in some cancer patients, DFO has shown little activity. Considering these results, we have developed a new group of chelators that show far greater activity than DFO at inhibiting cancer cell growth. These studies have been published in high quality journals such as BLOOD (Richardson et al. 1995, 1997, 1999) and form the basis for the current study. In this study we will examine how these iron-binding drugs work to inhibit the growth of cancer cells compared to their normal counterparts. These studies are important for the rational design of even more effective chelators. Recent studies in my lab have shown that our new chelators have far greater activity than a drug currently used to treat leukemia, known as hydroxyurea (HU). Our studies also show that the chelators act by a variety of mechanisms, explaining their greater activity than HU. Furthermore, we have shown that these chelators show significant anti-tumour activity in mice. The potential of this form of therapy has been confirmed by the entrance of the chelator, Triapine, into clinical trials (Vion Pharmaceuticals, USA). Our chelators are more effective than Triapine, thus, the present project is crucial for developing novel anti-tumour therapies.Read moreRead less
RNA interference is a newly discovered means by which we are able to turn off cancer-causing genes with high precision. However, it is difficult to get the drug to every cancer cell. Therefore we are designing and testing new RNA interference molecules that are able to alert the immune system to the presence of the cancer thus causing its elimination. This will prove to be a more effective cancer treatment than current therapies.
One of the hallmarks of cancer cells is their ability to divide and multiply in an uncontrolled manner. Specific proteins that make up the skeleton of cells (cytoskeleton) play an important part in the cell division process and as such make extremely important targets for anticancer therapy. Our research is developing ways to best target cell division proteins so that we can make drug resistant cancer cells sensitive to chemotherapy.
In cancer cells the normal process of cell death (called apoptosis) is defective, helping abnormal cells to grow and multiply unchecked. The Bak protein is a member of the Bcl-2 family of apoptosis regulators, and plays a pivotal role in mediating cell death. By defining each step in Bak-mediated apoptosis, we aim to better understand how cancer cells accumulate, and how targeting the Bcl-2 family may lead to effective anti-cancer therapeutics.
Role Of Bak And Bax Membrane Anchors In Targeting And Apoptotic Pore Formation.
Funder
National Health and Medical Research Council
Funding Amount
$352,319.00
Summary
In cancer cells the normal process of cell death (called apoptosis) is defective, helping abnormal cells to grow and multiply unchecked. The Bak and Bax proteins are members of the Bcl-2 family of apoptosis regulators, and play a pivotal role in mediating cell death. By defining how these proteins form a pore in mitochondria, the point of no return in cell death, will help the development of novel anti-cancer agents that target the Bcl-2 family in general, and Bak and Bax in particular.
Non-viral Vectors For Targeted Delivery Of RNAi Nucleotides To Cervical Cancers
Funder
National Health and Medical Research Council
Funding Amount
$415,738.00
Summary
RNA interference (or gene silencing) is a new technique whereby we are able to turn off the expression of a particular gene either temporarily or permanently. Cancer is basically a genetic disease where certain protective genes are lost or cancer-causing genes expressed. Gene silencing holds great promise in the treatment of genetic disorders, infectious diseases and cancer. Cervical cancer is caused by infection with the human papillomavirus and the expression of two cancer-causing genes. Using ....RNA interference (or gene silencing) is a new technique whereby we are able to turn off the expression of a particular gene either temporarily or permanently. Cancer is basically a genetic disease where certain protective genes are lost or cancer-causing genes expressed. Gene silencing holds great promise in the treatment of genetic disorders, infectious diseases and cancer. Cervical cancer is caused by infection with the human papillomavirus and the expression of two cancer-causing genes. Using RNA interference we can turn off the expression of these two genes which results in the death of the cancer cell. We are also able to cure mice of tumours derived from human cervical cancer. The major issue with gene silencing is how to deliver it effectively to patients. Here we are investigating novel nanoparticulate systems to deliver this new gene-inhibiting drugs preferentially to the tumour site.Read moreRead less
BMP4 - A Metastasis Suppressor Gene In Breast Cancer
Funder
National Health and Medical Research Council
Funding Amount
$454,220.00
Summary
Breast cancer is the most common cause of cancer death in western women. Whilst the primary tumour can often be eradicated successfully, in many cases, it may have already spread to other organs, including lungs, liver and bone, causing severe morbidity. Current treatments are largely palliative and new therapies that specifically prevent to spread of breast cancer are urgently required. However, little is known about the molecular pathways regulating the spread of cancer cells. We have shown th ....Breast cancer is the most common cause of cancer death in western women. Whilst the primary tumour can often be eradicated successfully, in many cases, it may have already spread to other organs, including lungs, liver and bone, causing severe morbidity. Current treatments are largely palliative and new therapies that specifically prevent to spread of breast cancer are urgently required. However, little is known about the molecular pathways regulating the spread of cancer cells. We have shown that expression of a gene called BMP4 in tumours blocks the spread of breast cancer in a mouse model. The aim of this project is to develop the application of BMP4 as a therapy for advanced breast cancer using our mouse model. We will measure the expression of BMP4 in human breast cancer and test whether treatment with purified BMP4 protein can protect mice from the spread of breast cancer. If successful, this study will offer a new therapy for women with currently incurable breast cancer.Read moreRead less
Modulating Interactions Between TNFalpha And IGF-1 Signaling Pathways To Reduce Necrosis Of Dystrophic Muscle
Funder
National Health and Medical Research Council
Funding Amount
$476,515.00
Summary
Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attracti ....Duchene Muscular Dystrophy (DMD) is a lethal childhood disease that affects mainly boys. These experiments will test new highly specific anti-inflammatory drugs for the potential clinical treatment of muscular dystrophies, using the mdx mouse model of human DMD. It is essential that the benefits of such anti-inflammatory drugs are fully evaluated in long term studies in mice. Two of these drugs (Enbrel and Remicade) are already in wide clinical use for inflammatory disorders and present attractive options for treatment of DMD patients due to their high specificity of action and relatively few side effects. We have shown that both of these drugs have a striking protective effect and reduce necrosis of dystrophic muscle in the mdx mouse. The benefits of these drugs (and the mouse equivalent cVIq) is due to blocking the action of the key pro-inflammatory cytokine Tumour Necrosis Factor-alpha (TNFa). However, the precise mechanism by which high levels of TNFa increase necrosis of dystrophic muscle is not clear. There are many possible pathways. Identifying which is the key pathway(s), is of central importance to design and target new drugs to treat such lethal muscle diseases. Such modulation of signalling is a major therapeutic goal. To determine which mechanism of TNFa action is responsible for muscle necrosis, experiments will investigate several signalling pathways using specific inhibitors: the drug Pifithrin to inhibit p53; soluble RAGE to block RAGE (Receptor for Advanced Glycation Endproducts); and specific inhibitory peptides to block JNK (c-Jun N-terminal kinase). The application of these inhibitors (drugs), in mice, as future therapies for muscle diseases is novel. These studies will provide much new information on TNFa related signalling that is highly relevant to the potential treatment of many diseases, including muscle wasting that is a major problem in the ageing population and in disuse atrophy and cachexia.Read moreRead less