Identifying The Targets Of MiRNA Regulation In Cancer
Funder
National Health and Medical Research Council
Funding Amount
$290,600.00
Summary
microRNAs are noncoding RNAs with fundamental functions in biology and significant roles disease. microRNAs control gene expression by destroying RNA or controlling its translation into cellular proteins. To determine how certain microRNAs cause human disease it is essential to know their RNA targets. We are developing methods to identify these targets and aim to apply these methods to identify the targets of microRNAs with known roles in cancer.
Interactions Between Hedgehog And Ras Signaling In Lung Adenocarcinoma
Funder
National Health and Medical Research Council
Funding Amount
$295,983.00
Summary
Lung cancer is a common and lethal disease in our community. In this project, we explore how signaling pathways that regulate the development of the lung in embryos contribute to the initation and progression of lung cancer. To do this, we use a mouse model of lung cancer in which we can activate embryonic signaling pathways in adult mice to study there effect on the disease. Understanding these pathways will help us to better treat and prevent lung cancer in humans.
DNA Damage Induced By UVA And UVB In Squamous Cell Carcinoma Progression
Funder
National Health and Medical Research Council
Funding Amount
$65,000.00
Summary
Australia has the highest incidence of skin cancer in the world. This results from immigration of individuals with fair skin to Australia. Skin cancer is three times as common as all other cancers combined. Overall, the incidence of skin cancer continues to rise in Australia and it will be several years before the true effectiveness of preventative programs are known. In the meantime, 1000 Australians die each year from skin cancer. Modern sunscreens, even those with high SPF and labelled as bro ....Australia has the highest incidence of skin cancer in the world. This results from immigration of individuals with fair skin to Australia. Skin cancer is three times as common as all other cancers combined. Overall, the incidence of skin cancer continues to rise in Australia and it will be several years before the true effectiveness of preventative programs are known. In the meantime, 1000 Australians die each year from skin cancer. Modern sunscreens, even those with high SPF and labelled as broad spectrum do not protect very well from UVA, though they are very effective UVB filters. Most sunscreens absorb or reflect only about 50% as much UVA as UVB. Thus sunscreen use alters the spectrum of UV received. This is an important issue, because if sunscreens are used to prolong sun exposure they will selectively increase the amount of UVA reaching the skin, and the sun contains a lot more UVA than UVB. There is only limited evidence to suggest they protect from skin cancer in humans whereas there is good evidence that they protect from precursor lesions. We have developed a new hypothesis, that UVB is primarily responsible for development of preneoplastic lesions (solar keratosis and dysplastic nevi) whereas UVA plays a relatively more important role in their progression to malignancy. This hypothesis would explain why sunscreens are more effective at preventing nevi and solar keratosis formation than they are at preventing melanoma and squamous cell carcinoma. Until the action spectrum defining the wavelengths responsible for skin cancer induction is known, the optimal methods for protection from skin cancer will be difficult if not impossible to design. That different wavelengths may be involved in different phases of skin cancer development in humans is a novel hypothesis: if it is correct it will have profound implications for both the design of sunscreens and our current public health programmes for skin cancer prevention.Read moreRead less
Development Of Anti-metastatic And Tumour Targeting Reagents By Design Of Inhibitors To Specific Eph/ephrin Cell-cell
Funder
National Health and Medical Research Council
Funding Amount
$200,000.00
Summary
Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (E ....Metastatic disease, malignant melanoma in particular, is a health issue of considerable global importance with 1,000 fatal melanoma cases- year in Australia alone. While progress has been made on prevention and early diagnosis, no curative treatment exists for stage IV melanoma. Tumour progression and the acquisition of metastatic competence primarily reflect dysregulation of cell adhesion and cell motility rather than proliferation and survival. In this context, Eph receptor tyrosine kinases (Ephs) and their membrane-bound ephrin ligands are crucial mediators of cell adhesion and motility and are notably overexpressed in metastatic tumours rather than primary (benign) lesions5. Our laboratories were the first to identify EphA3 7, and one of the first to isolate its ligand, ephrin-A5. EphA3 was isolated from acute lymphoblastoid leukemia and malignant melanoma patients, where increasing expression levels correlate with metastatic progression. Soluble, non-clustered forms of Ephs and ephrins are effective inhibitors of Eph activity 3 and provide opportunities to generate specific drugs for cancer therapy. We now propose a research and development program for the development of EphA3-specific drugs and their production for pre-clinical and clinical evaluation for placement onto a national and international market.Read moreRead less
Identification And Functional Evaluation Of MicroRNAs And Their Target Genes That Regulate Breast Cancer Metastasis
Funder
National Health and Medical Research Council
Funding Amount
$607,773.00
Summary
Breast cancer is the major cause of cancer-associated death in Australian women. Once the disease has spread to other organs, as occurs in about 20% of cases, our ability to treat the disease is limited and mortality is high, leading to an enormous social and economic cost New therapies for advanced disease are needed urgently. To facilitate this, we need to understand the molecular regulation of metastasis to distant organs and use this knowledge to develop new molecular targeted therapies.
The Role Of The EphA1 In The Normal Epithelial Organs And In Epithelial Tumour Progression.
Funder
National Health and Medical Research Council
Funding Amount
$564,500.00
Summary
The Eph family of proteins were initially found to be important in normal development. In humans this corresponds to the first 12 weeks of pregnancy. In parallel with these studies, other work provided evidence of abnormally high levels of these proteins in a number of human cancers. More recent evidence suggests that these proteins have important roles in the maintenance of normal tissues and in non-malignant diseases. This proposal seeks to understand how one of these proteins (EphA1) works in ....The Eph family of proteins were initially found to be important in normal development. In humans this corresponds to the first 12 weeks of pregnancy. In parallel with these studies, other work provided evidence of abnormally high levels of these proteins in a number of human cancers. More recent evidence suggests that these proteins have important roles in the maintenance of normal tissues and in non-malignant diseases. This proposal seeks to understand how one of these proteins (EphA1) works in the cells which form the skin, liver, kidneys, breast and prostate. These cells also form the lining of the mouth, stomach, bowel and lungs. Understanding how the EphA1 protein and other members of this family cooperate to control the development and maintenance of these organs will allow us to determine whether this protein might be involved in congenital defects and diseases in these organs (such as kidney failure, cirrhosis of the liver and skin diseases). A second main aim of this project is to explore further the observation that Eph proteins are abnormally highly expressed in a wide rangre of human cancers. This abnormal expression is directly correlated with the tumours spreading throughout the body. EphA1 is abnormally highly expressed in cancers of the bowel, lung, breast and prostate. These are the commonest cancers in man and some of the most difficult to treat. The work proposed asks how EphA1 contributes to the development and progression of these cancers. These results will have very direct implications for the development of therapies which target the EphA1 protein.Read moreRead less
Understanding The Development Of Pancreatic Islet Cell Tumours
Funder
National Health and Medical Research Council
Funding Amount
$579,163.00
Summary
We will use mouse models of pancreatic cancer that we have established previously to investigate the molecular basis of the development and progression of tumours in the insulin-producing cells of the pancreas. We propose to manipulate a small number of candidate genes using established islet cultures and new mouse models in order to characterise the effect they have on islet cell biology and tumorigenesis.
Mechanism Of Breast Cancer Metastasis: Tumour Cell Remodelling Of The Extracellular Matrix
Funder
National Health and Medical Research Council
Funding Amount
$377,331.00
Summary
The main complication in breast cancers leading to death is metastatic relapse. This research aims to understand the role for a protease that promotes spread of breast cancer to the lymph nodes and lungs. The outcomes will identify a novel process that leads to lymph node metastasis and offer a new target for therapies that prevent relapse and tests to identify breast cancer patients at risk of relapse.
The Assessment Of Clinical And Molecular Adjunctive Tools For The Early Detection Of Oral Mucosal Neoplasia
Funder
National Health and Medical Research Council
Funding Amount
$454,383.00
Summary
It is anticipated that this research will make a significant contribution to our understanding of the natural development of oral cancer and will thus have a direct benefit to patients. The proposed research will enable high quality genetic analysis of individual mutations of relevance to oral cancer via a rapid, reliable, economic, and sensitive screening assay for the assessment of a large number of suspicious oral mucosal lesions.
Androgen-regulated Proteins: Predictors Of Prostate Cancer Development And Progression
Funder
National Health and Medical Research Council
Funding Amount
$391,073.00
Summary
Use of PSA (prostate specific antigen) levels in blood to screen for prostate cancer has resulted in a) earlier detection of tumours and b) increased diagnosis of a premalignant disease of the prostate called PIN (prostatic intraepithelial neoplasia). PIN is thought to progressively change into cancer, which can invade the rest of the body. Growth of the cells of the prostate is regulated by male hormones called androgens. Small cancers localised to the prostate grow in response to androgens, bu ....Use of PSA (prostate specific antigen) levels in blood to screen for prostate cancer has resulted in a) earlier detection of tumours and b) increased diagnosis of a premalignant disease of the prostate called PIN (prostatic intraepithelial neoplasia). PIN is thought to progressively change into cancer, which can invade the rest of the body. Growth of the cells of the prostate is regulated by male hormones called androgens. Small cancers localised to the prostate grow in response to androgens, but larger cancers which have spread from the prostate grow steadily even after the androgen supply is cut off by removal of the testicles. In this project we will examine changes in the level of various proteins in the prostate, which are known to be produced in response to androgen, to see whether they discriminate: 1) those patients with PIN who will go on to develop prostate cancer, 2) those patients with small cancers within the prostate who progress to widespread cancer. We also propose to use a laser-controlled dissecting microscope to obtain pure populations of cancer cells from prostate tissues and then to isolate their DNA in order to: a) examine the DNA sequence of the protein which controls cellular growth in response to androgen (ie the androgen receptor) to see whether undesirable changes (mutations) have occurred in its structure during the development of the cancer, and b) identify proteins which mediate the effects of the androgen regulated proteins and control cancer development or spread. This will be done using the revolutionary technique of gene microarrays, where partial DNA sequences of approximately 4,000 different prostate genes are spotted onto small membrane filters, and which enable identification of genes that change in level with the onset of cancer and cancer spread. These 2 objectives will, in the case of a) prevent inappropriate treatment for prostate cancer, and b) identify targets for new treatments and for chemoprevention.Read moreRead less