Our objective is to understand the biological significance of the interaction between iron and the hormone gastrin. The project's significance to human health lies in the fact that gastrins stimulate growth of the lining of the stomach and colon, accelerate the development of gastrointestinal cancers, and may be involved in iron homeostasis. Recognition that iron is essential for the biological activity of gastrins may allow the development of novel therapies for colon cancer and iron overload.
Progastrin Derived Peptides: Biological Activities And Functions In The Gastrointestinal Tract
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
Gastrin is a hormone from the stomach which aids digestion by stimulating acid secretion. However too much acid can cause ulcers of the gastrointestinal tract. Gastrin also stimulates the growth of the lining of the stomach and intestines. This growth promoting effect is important for the development of the gastrointestinal tract before birth and may also be involved in a number of cancers especially colon cancer. Several different forms of gastrin are made by endocrine cells of the stomach and ....Gastrin is a hormone from the stomach which aids digestion by stimulating acid secretion. However too much acid can cause ulcers of the gastrointestinal tract. Gastrin also stimulates the growth of the lining of the stomach and intestines. This growth promoting effect is important for the development of the gastrointestinal tract before birth and may also be involved in a number of cancers especially colon cancer. Several different forms of gastrin are made by endocrine cells of the stomach and by cancers of the colon. It seems that the different types of gastrins have different effects and act through distinct receptors, but we do not know which are the most important forms and whether all forms are biologically active. The amount, type and activity of the different gastrins, and the regions of the molecule that are essential for biological activity, will be investigated using cell lines, animal models that overproduce too much gastrin, animal models of colon cancer and in patients with colon cancer. Colorectal carcinoma (cancer of the large bowel) is the second most common cause of cancer death. A successful outcome will result in the development of assays for the early diagnosis and monitoring of bowel cancer and the potential for novel treatments such as gastrin receptor antagonists and radiolabelled gastrin analogues for radiotherapy.Read moreRead less
The objective of this project is to understand the biological significance of the complex between ferric ions and non-amidated gastrins (NAGs). This laboratory has shown that NAGs selectively bind 2 ferric ions, and that ferric ion binding is essential for biological activity. Our unpublished data in mouse models indicates a previously unsuspected reciprocal relationship between plasma NAG concentrations and iron status. The significance of this project to human health lies in the facts that NAG ....The objective of this project is to understand the biological significance of the complex between ferric ions and non-amidated gastrins (NAGs). This laboratory has shown that NAGs selectively bind 2 ferric ions, and that ferric ion binding is essential for biological activity. Our unpublished data in mouse models indicates a previously unsuspected reciprocal relationship between plasma NAG concentrations and iron status. The significance of this project to human health lies in the facts that NAGs act as growth factors for the normal gastric and colonic mucosa, accelerate the development of both gastric and colorectal cancer, and may be involved in iron overload. The specific aims are: (1) to determine whether or not ferric ions are essential for the stimulation of colorectal carcinoma (CRC) development by NAGs in vivo, (2) to develop orally active NAG inhibitors and analogues, and (3) to confirm the relationship between NAGs and iron status in mice and extend these observations to humans. The research design mirrors the specific aims, and utilises the unique combination of skills of the chief and associate investigators. Firstly, agents (desferrioxamine and bismuth ions) known to block the binding of ferric ions to NAGs will be tested as NAG inhibitors in 4 animal models of CRC development. Secondly, orally active relatives of desferrioxamine and structurally modified gastrin fragments will be tested in CRC cells and in animal CRC models as NAG inhibitors and analogues, respectively. Thirdly, serum gastrins will be measured in mice with altered dietary iron uptake, and in patients with iron overload. These studies are expected to confirm the reciprocal relationship between gastrin concentrations and ferric ion homeostasis observed in mice, and to demonstrate that a similar connection exists in humans. Recognition that metal ions are essential for the biological activity of NAGs may permit the development of novel therapies for colon cancer and iron overload.Read moreRead less
Cognitive Function And Fatigue In Cancer Patients After Chemotherapy
Funder
National Health and Medical Research Council
Funding Amount
$246,412.00
Summary
Many patients complain of tiredness after chemotherapy and some experience problems with memory, concentration, thinking and other aspects of mental function. Studies have confirmed that some women with breast cancer suffer these effects after chemotherapy and that they can last a long time. Although generally subtle they can affect quality of life and ability to function. Little is known about the causes of these side-effects. Possible causes include blood clotting in small vessels of the brain ....Many patients complain of tiredness after chemotherapy and some experience problems with memory, concentration, thinking and other aspects of mental function. Studies have confirmed that some women with breast cancer suffer these effects after chemotherapy and that they can last a long time. Although generally subtle they can affect quality of life and ability to function. Little is known about the causes of these side-effects. Possible causes include blood clotting in small vessels of the brain and release of molecules called cytokines, as a result of chemotherapy. Hormonal changes and induced menopause might also contribute to these effects in women. Here we propose to evaluate men and women who either receive chemotherapy to prevent recurrence of colorectal cancer, or who are followed without such treatment after surgery. Patients will complete a questionnaire that assesses their level of fatigue and participate in tests of mental functioning, before, during and at intervals after treatment. Possible causes of fatigue and cognitive problems will be studied by measuring products in the blod that indicate blood clotting, levels of cytokine molecules that might cause these symptoms and levels of sex hormones in both men and women. This may lead to further studies to help reduce the burden of fatigue and cognitive impairment from chemotherapy. The goals of our study are to provide comphrehensive information about important side-effects of cancer treatment and to examine the mechanisms that may cause them. This information is important for supporting people living with cancer and for subsequent research to develop interventions that will promote healthy lifestyles during and after treatment for cancer.Read moreRead less
The Mechanism Of Action Of Progastrins In Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$378,000.00
Summary
Clear evidence now links precursors of the hormone gastrin with the development of colorectal cancer (CRC). Elevated gastrin concentrations in the blood increase the risk of developing CRC, and in patients with CRC blood gastrin concentrations are higher than normal. Furthermore experiments in animals indicate that gastrin precursors stimulate growth of the cells lining the interior of the colon. The major challenges in this field are to characterise the proteins (called receptors) which bind ga ....Clear evidence now links precursors of the hormone gastrin with the development of colorectal cancer (CRC). Elevated gastrin concentrations in the blood increase the risk of developing CRC, and in patients with CRC blood gastrin concentrations are higher than normal. Furthermore experiments in animals indicate that gastrin precursors stimulate growth of the cells lining the interior of the colon. The major challenges in this field are to characterise the proteins (called receptors) which bind gastrin precursors to the surface of colon cells, and to understand how receptor binding triggers changes in the colon which result in CRC development. Our recent discovery that gastrin precursors promote cell migration by reducing adhesion between cells is particularly significant from the perspective of CRC because of the potential importance of this phenomenon in the early stages of cancer development. Our recent observation that gastrin precursors bind metal ions with high affinity further suggests that metal binding may be essential for receptor binding and hence for biological activity. We will therefore investigate: (1) whether binding of metal ions to gastrin precursors effects biological activity, (2) which regions of gastrin precursors are required for receptor binding, (3) the structures of the receptors which bind gastrin precursors to colon cells, (4) the pathways which connect the receptors to other intracellular proteins that maintain contact between adjacent cells, and (5) the differences between the pathways controlling adhesion and the pathways controlling cell growth. This project should lead to a detailed understanding of the molecular mechanisms underlying the effect of gastrin precursors on colon cell growth and adhesion. Definition of the receptors and intracellular signalling mechanisms involved may ultimately lead to novel treatments for disorders of colonic proliferation including CRC.Read moreRead less
CpG Island Methylation In Microsatellite Stable Colorectal Cancers: Epigenetics Or Epiphenomenon?
Funder
National Health and Medical Research Council
Funding Amount
$245,402.00
Summary
For years researchers have known that changes in the sequence of DNA in genes within a cell can lead to cancer, particularly when those changes are passed on to daughter cells. This has lead to massive research interest in the field of cancer genetics. In the last few years, it has become clear that as well as changes in DNA, other more subtle changes can be passed on. These changes, which do not directly involve changes in DNA sequence, are referred to as epigenetic changes. One of the most com ....For years researchers have known that changes in the sequence of DNA in genes within a cell can lead to cancer, particularly when those changes are passed on to daughter cells. This has lead to massive research interest in the field of cancer genetics. In the last few years, it has become clear that as well as changes in DNA, other more subtle changes can be passed on. These changes, which do not directly involve changes in DNA sequence, are referred to as epigenetic changes. One of the most commonly recognised epigenetic changes is known as methylation. Methylation of genes can switch that gene off, meaning that the protein normally made is no longer present in the cell. This can have profound effects on the way cells behave, and importantly may be involved in the development of cancer. In this study, we will look at a group of colorectal cancers that show abnormally high amounts of DNA methylation , to test our hypothesis that these cancers share a common origin that is distinct from the usual type of bowel cancer. The findings will be important, as they may allow us to show that all bowel cancers are not the same, and that simple gene testing may be able to identify the different subtypes. If bowel cancers can be classified according to the way in which they have developed, then this will help us to understand what causes them why some are more aggressive than others, and why some may respond differently to existing or future cancer treatments.Read moreRead less
Elucidation Of Mechanisms By Which Fibre Promotes Or Protects From Colorectal Tumorigenesis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
In a carefully controlled animal model of colon cancer development, dietary fibre can increase or decrease the likelihood of colon cancer development. It depends upon the type of fibre being fed to the animal. The mechanisms by which fibres can increase or decrease the likelihood of colon cancer developing are, however, poorly understood. In this proposal, we will attempt to elucidate at least some of the mechanisms. We plan to define whether animals consuming fibres that increase cancer develop ....In a carefully controlled animal model of colon cancer development, dietary fibre can increase or decrease the likelihood of colon cancer development. It depends upon the type of fibre being fed to the animal. The mechanisms by which fibres can increase or decrease the likelihood of colon cancer developing are, however, poorly understood. In this proposal, we will attempt to elucidate at least some of the mechanisms. We plan to define whether animals consuming fibres that increase cancer development have factors in their faeces that affect the health of the cells that line the colon (the ones that form the cancers). This will be examined in both the test tube and in healthy rats. Whether fibres influence the access of these factors to the lining cells by sequestering or hiding the factors in the jelly-like consistency some fibres produce in the colon will also be examined. The results will help identify conditions in the faeces that alter the susceptibility of colons to developing cancer. By identifying these conditions, we can then apply our knowledge to human subjects, so that we might be able to identify those at a higher or lower risk of developing colon cancer and we can advise and (subsequently prove) ways of modifying diet to reduce the risk of colon cancer.Read moreRead less
Regulation Of Mutational Load By Chemopreventive Agents And Implications For Molecular Pathogenesis Of Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$423,750.00
Summary
In Australia colorectal cancer is the second most common cause of cancer death, however the morbidity and mortality of colorectal cancer is currently not under control. Identification of safe and practical preventive agents should aid control. There is increasing evidence that colorectal cancer is associated with endogenous (internall) and exogenous (external) factors. They cause damage to DNA which might lead to tumour development if the damage is not repaired. This study will first identify th ....In Australia colorectal cancer is the second most common cause of cancer death, however the morbidity and mortality of colorectal cancer is currently not under control. Identification of safe and practical preventive agents should aid control. There is increasing evidence that colorectal cancer is associated with endogenous (internall) and exogenous (external) factors. They cause damage to DNA which might lead to tumour development if the damage is not repaired. This study will first identify the ability of preventive agents (aspirin-like drugs, fish oil, and antioxidants) to regulate DNA damage, then examine the effect of combination of the agents. It will finally determine the ability of agents, or combination of agents, to prevent development of colorectal cancer using two animal models. Prevention of human CRC by such a strategy should be feasible. First, evidence indicates that DNA damage is important in tumour initiation. Second, exogenous regulation of DNA damage, repair and removal seems possible. Epidemiological studies have suggested that that 30-70% of cancer can potentially be prevented with proper adjustment of diets (fat, fibre, resistant starch) and supplements of drugs (NSAIDs) or antioxidants (Vitamin, Selenium). Third, preventive strategies are likely to be feasible. At the population level, they would need to be safe and manageable in the context of dietary lifestyle, but this can be achieved through a range of food technology developments. In individuals at high risk, personalised preventive strategies become feasible through doctor-patient contact. This study focuses on regulation of DNA damage, and its repair and removal during the early stage of tumour development. The study will provide information if preventive agents, alone or in combination, provide a promising strategy for colorectal cancer through reduction of genetic damage. They might also identify new biomarkers that facilitate testing in humans.Read moreRead less
A Randomised Trial Of Preoperative Radiotherapy For Stage T3 Adenocarcinoma Of Rectum
Funder
National Health and Medical Research Council
Funding Amount
$521,220.00
Summary
The most appropriate management of locally advanced rectal cancer is controversial as evident by various treatment options available and used. It remains unclear whether pre-operative radiotherapy, and if so what form of therapy, is required for this group of patients. The first aim of this trial is to see whether a long course of radiotherapy with chemotherapy is superior to a short course of radiotherapy. The second aim is to see whether the advantage of pre-operative radiotherapy remains with ....The most appropriate management of locally advanced rectal cancer is controversial as evident by various treatment options available and used. It remains unclear whether pre-operative radiotherapy, and if so what form of therapy, is required for this group of patients. The first aim of this trial is to see whether a long course of radiotherapy with chemotherapy is superior to a short course of radiotherapy. The second aim is to see whether the advantage of pre-operative radiotherapy remains with modern surgical technique. Colorectal cancer is the commonest cancer in Australia and local recurrence leads to severe morbidity with no effective treatment for permanent control. It is important, therefore, to establish treatment regimens that will minimize the risk of local recurrence and it will be significant if this trial can establish that pre-operative radiotherapy can achieve this with minimal toxicity. The quality of life associated with each of the three arms of the trial has not been adequately addressed and will be studied here. The result of this trial will influence designs of future trials if one or other of the pre-operative regimens is shown to be effective. The two regimens, Short Course and Long Course , represent opposing philosophies: minimize the overall treatment time (2 weeks from start of radiotherapy to surgery) to avoid accelerated repopulation versus give more intensive therapy and utilise the sensitising effect from 5-FU on radiotherapy to obtain greater tumour cell kill probability. If one regimen proves more effective than the other, the design of future trials and the way of thinking about the biology will be influenced. There may be implications for the cost of treatment of this disease: Long Course is much about five times more expensive to deliver than Short Ccourse.Read moreRead less