Precision Prevention Of Colorectal Cancer: Understanding Tumourigenesis In High Risk People To Optimise Prevention
Funder
National Health and Medical Research Council
Funding Amount
$1,562,250.00
Summary
Bowel cancer, Australia’s second most common cause of cancer death, is one of the most preventable cancers. We know some people have a high risk because they carry changes in their DNA, or they have many pre-cancerous growths (polyps). Bowel cancer is increasing in young people, before 50 years of age, with no known reason. If we can identify people who have a high risk and understand how and why it develops in young Australians, we can prevent these cancers.
Identification Of Novel Colorectal Cancer Susceptibility Genes
Funder
National Health and Medical Research Council
Funding Amount
$358,093.00
Summary
Colon cancer is one of the most common cancers, with around 1 million cases diagnosed annually. These cancers can be caused by a combination of lifestyle/environmental and genetic factors. Genetics cause ~30% of colon cancers, although the cause is unexplained in ~2/3 of these cases. The aim of this project is to discover new colon cancer genes by extensive gene sequencing of multi-case unexplained colon cancer families, and screening of additional cases and cancer-free individuals.
Overcoming Resistance To Anti-EGFR Antibody Therapy In Colorectal Cancer Using Novel Targeted PI3K And MEK Inhibitors
Funder
National Health and Medical Research Council
Funding Amount
$466,586.00
Summary
Cetuximab treatment is a standard of care for metastatic colorectal cancer, but patients with KRAS, BRAF, PIK3CA or PTEN gene mutated tumours show a lack of response. Newly developed targeted inhibitors against PI3K and MEK may overcome cetuximab resistance. We will perform preclinical studies in cell lines representing the range of mutated tumours found in patients to compare the efficacy of these novel treatments with cetuximab and to characterise the mechanisms underlying drug action.
Defining Iron And Haem-induced Pro-carcinogenic Pathways Of Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$566,277.00
Summary
Colorectal cancer is very common in Western society. Population studies have reported that high consumption iron-containing foods and red meat, the latter being a source of both haem and iron, are risk factors for colorectal cancer. This study will identify the levels of dietary haem and iron that promote colorectal cancer development. Also, it will determine the mechanisms and relative contribution of iron and haem to pro-carcinogenic pathways that result in colorectal cancer.
Genomic Profiling For The Prevention Of Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$425,048.00
Summary
Bowel cancer is a major health issue but is also a preventable disease. Identifying who has a high risk of developing bowel cancer from someone who has a low risk is an important way to ensure preventative medical treatment is targeted to those who are at the highest risk and will ultimately save lives. I will utilise different genomic profiling approaches to identify risk factors for bowel cancer so that they can be used to identify high risk people in the population.
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
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
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