There is an ongoing need for the development of new anticancer drugs, particularly those directed against solid tumours. In the past plants have been an extremely valuable source of anticancer agents, including the world s best selling anticancer drug, Taxol, isolated from the Pacific Yew tree. However, such molecules are typically complex and often very expensive to manufacture or extract from natural sources. So far very little attention has been paid to protein-based molecules from plants as ....There is an ongoing need for the development of new anticancer drugs, particularly those directed against solid tumours. In the past plants have been an extremely valuable source of anticancer agents, including the world s best selling anticancer drug, Taxol, isolated from the Pacific Yew tree. However, such molecules are typically complex and often very expensive to manufacture or extract from natural sources. So far very little attention has been paid to protein-based molecules from plants as potential anticancer agents because pharmaceutical companies have focused on organic molecules. In principle protein-based molecules could be produced much more cheaply and thus made available more widely to patients than existing drugs. All that is required are the lead molecules, or proteins that display sufficient anticancer activity to be used as the basis for further optimization. We have discovered a family of plant proteins called the cyclotides that have recently been shown to have considerable promise as anticancer agents. In the current project we will use synthetic chemistry to modify selected amino acids on the surface of this new family of proteins to determine which parts of the molecules are responsible for their activity. We will use this information to design improved analogues. The project is a collaboration between researchers at the Institute for Molecular Bioscience, University of Queensland, who have expertise in the required peptide chemistry and researchers and clinicians at Uppsala University, Sweden who have a range of assays and clinical expertise to test the new molecules. Both groups have been centrally involved in the discovery of the cyclotide family of plant proteins and are committed to developing them as exciting new anticancer agents.Read moreRead less
Advanced Anti-cancer Activities With Therapeutic Agents That Induce Tumor Cell Apoptosis And Antitumor Immune Responses.
Funder
National Health and Medical Research Council
Funding Amount
$85,701.00
Summary
The aim is to perform pre-clinical studies to identify new therapies for blood cancers. We will utilise three new anti-cancer agents that kill tumor cells and genetically engineered mice that develop cancer. We will determine if these three new agents kill the mouse tumor cells and activate anti-tumor immunity. The combined effect of killing blood cancer cells using new therapeutics, coupled with enhancing the anti-cancer immune response may hold the key to developing new treatments.
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
I am a molecular biologist interested in understanding how cells are able to actively kill themselves, and how cells make the decision to live or die. Understanding how cells kill themselves will ultimately lead to better therapies designed to kill cancer
Role Of Transformation And IAPs In Sensitivity Of Cells To TNFalpha
Funder
National Health and Medical Research Council
Funding Amount
$505,786.00
Summary
Current cancer treatments are ineffective and unpleasant for patients. This is because existing cancer treatments target normal as well as cancer cells. New anti-cancer drugs have been designed to encourage cancer cells to kill themselves, by a process called apoptosis, but may still target normal cells. This project aims to discover why cancer cells are susceptible to a novel anti-cancer drug and a natural ligand called TNF but normal cells are not. This will lead to better treatments.
Investigation Of A Tumour Enzyme As A Predictor Of Patient Response To An Australian Anti-cancer Drug
Funder
National Health and Medical Research Council
Funding Amount
$362,082.00
Summary
GSAO is a new cancer drug we have developed that is currently being trialed in cancer patients. Our investigation of how GSAO works has revealed that it needs to be activated by an enzyme expressed by certain types of cancers. This finding implies that GSAO should be more effective against cancers that make this enzyme. Our aim is to establish this concept in laboratory based experiments as a basis for selection of patients who are more likely to benefit from GSAO treatment.
Apo2L/TRAIL Killing Of Tumour Cells And The Role Of Inhibitor Of Apoptosis Proteins
Funder
National Health and Medical Research Council
Funding Amount
$390,321.00
Summary
Melanomas and Gliomas are tumour types that respond poorly to current treatments. Current treatments are not only sometimes ineffective, but also unpleasant and may cause co-lateral damage. We will test 2 new targetted anti-cancer treatments, that so far appear to have minor side effects in small animal models, on these difficult to treat tumour types to see if and how they kill them. We also want to know whether these independent treatments can work together to kill tumours more effectively. Al ....Melanomas and Gliomas are tumour types that respond poorly to current treatments. Current treatments are not only sometimes ineffective, but also unpleasant and may cause co-lateral damage. We will test 2 new targetted anti-cancer treatments, that so far appear to have minor side effects in small animal models, on these difficult to treat tumour types to see if and how they kill them. We also want to know whether these independent treatments can work together to kill tumours more effectively. Although we will not personally test these drugs in clinical settings, these drugs or similar are currently in preclinical and clinical trials. This means that understanding how these drugs function is of paramount importance and may result in better clinical trials and possibly more rapid acceptance of the use of these drugs in patients.Read moreRead less
2-Methoxyestradiol Analogues: Prototype Modulators Of Annexin II-dependent Plasminogen Activation
Funder
National Health and Medical Research Council
Funding Amount
$369,690.00
Summary
The enzyme system that enables us to dissolve blood clots is similar to the system that enables cancer cells to escape from the primary tumour and travel in the blood to another organ to form a secondary cancer growth. We have new results showing that some drug candidates can distinguish between these two closely related enzyme systems. We are now working to develop inhibitors that will stop cancer cells from spreading without compromising the ability to dissolve blood clots.