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
Peritoneal Metastases From Colorectal Carcinoma: Exploring The Potential Of Immunotherapy As A Treatment Adjunct
Funder
National Health and Medical Research Council
Funding Amount
$89,197.00
Summary
Twenty percent of patients with bowel cancer have disease involving the lining of the abdomen, called the peritoneum. These patients do poorly. The majority are inoperable, and chemotherapy has poor response in these patients. Therefore, there is a dire need to explore new treatments. Newer drugs that stimulate the immune cells to fight cancer have shown promise in other cancers. We aim to assess the potential of this treatment in peritoneal disease, with the aim of improving patient outcomes.
Population Genetics And Functional Genomics Approaches To Improve Outcomes For Patients With Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$466,492.00
Summary
Colorectal cancer (CRC) is the third leading cause of cancer related death in Australia, and the 5-year survival rate for metastatic disease remains below 10%. Over the next 4 years, my translational research program will focus on improving patient outcomes in four ways: Discovery of inherited variants affecting CRC risk and progression, tumour molecular classification, discovery of markers for prognosis and drug response, and elucidation of the molecular mechanisms driving CRC development.
Translational Genomics And Combinatorial Drug Discovery To Improve Outcomes For Patients With Colorectal Cancer
Funder
National Health and Medical Research Council
Funding Amount
$640,210.00
Summary
Bowel cancer is a major public health burden in Australia. Over the next 5 years, A/Prof Sieber’s research will focus on understanding the molecular pathology of bowel cancer and how this determines the course of disease and response to therapy. Integrated genomic, functional and drug discovery studies will provide significant new insights into fundamental tumour biology and open up new avenues for diagnosis and treatment.
Using A Novel Gut Culture System To Analyse The Influence Of Genes Mutated In Colon Cancer On Epithelial Cell Growth
Funder
National Health and Medical Research Council
Funding Amount
$436,650.00
Summary
Colorectal (or bowel) cancer is a major health problem in Australia. Approximately 1 in 21 Australians will develop the disease in his-her lifetime. The risk of bowel cancer increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for colorectal cancer are not very effective and the median survival for patients with this disease is poor at 7- 12 months. The development of colorectal cancer is complex and is affected by both genetic and environmenta ....Colorectal (or bowel) cancer is a major health problem in Australia. Approximately 1 in 21 Australians will develop the disease in his-her lifetime. The risk of bowel cancer increases with age, with the risk rising progressively and sharply from the age of 50. Current therapies for colorectal cancer are not very effective and the median survival for patients with this disease is poor at 7- 12 months. The development of colorectal cancer is complex and is affected by both genetic and environmental factors. Colorectal cancer progresses through a number of distinct pathological stages. This is thought to be the result of the progressive aquisition of mutations in genes that normally ensure a balance between cell growth and cell death. Mutations in a number of genes (known as APC, K-ras, p53, SMAD2, SMAD4) are commonly found in colorectal tumours. This research is aimed at understanding how genes which are altered in colon cancer influence the growth of cells in normal intestine. We have developed a system where normal mouse gut can be maintained and grown intact. Genes containing the alterations found in colon cancer will be introduced into the normal gut epithelial cells and the effects on the growth and behaviour of these cells analysed. This should improve our knowledge of how these altered genes contribute to the development of colon cancer.Read moreRead less