Identification Of Clinically Significant Subtypes Of Head And Neck Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$469,122.00
Summary
Squamous cell carcinoma of the head and neck region (HNSCC) is amongst the top 10 most prevalent cancers. It is a life threatening cancer that is associated with a mortality rate of approximately 40%. Whilst most patients are treated with a combination of surgery, radiation and chemotherapy a significant fraction of patients relapse and eventually succumb to the cancer. The molecular basis for relapse in these patients is still unknown. One possible explanation for treatment failure is the notio ....Squamous cell carcinoma of the head and neck region (HNSCC) is amongst the top 10 most prevalent cancers. It is a life threatening cancer that is associated with a mortality rate of approximately 40%. Whilst most patients are treated with a combination of surgery, radiation and chemotherapy a significant fraction of patients relapse and eventually succumb to the cancer. The molecular basis for relapse in these patients is still unknown. One possible explanation for treatment failure is the notion that the cancer contains biologically distinct subtypes of cancer cells. Some these cells may respond to therapy whilst a small fraction of cells may not. If this small fraction of resistant cells were able to divide and repopulate the tissue then this would provide an explanation for relapse in these patients. However, as yet no such data has been available to support this argument. Most recently, studies with another cancer called acute myelocytic leukaemia has shown that they do contain a small subtype of cancer cells that are resistant to therapy and can regenerate the disease in patients. These cells have been called tumour initiating cells (TIC). In this application we will use patient tumour samples to try to isolate TICs from HNSCC. We will first determine whether these TICs exist and whether they express markers of normal human stem cells. We will also test whether these TICs are more resistant to chemotherapeutics or radiation than the rest of the tumour cells. In addition we will enrich for these TICs and identify new protein markers that could be used to test patient samples before or after treatment. This would be of considerable assistance in making decisions about treatment choice or prognosis. Since TICs have not been reported in HNSCC previously their identification would lead to a considerable advance in our undesratnding of how these tumours form.Read moreRead less
Tumour Suppressor Networks: The Role Of SHIP-1 And Lyn In Suppressing Haematopoietic Tumours
Funder
National Health and Medical Research Council
Funding Amount
$469,526.00
Summary
Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in ....Haematopoietic malignancies kill a large number of Australians each year. Improving our understanding of the molecular mechanisms that underlie these diseases is essential for the design of more effective treatments. Lyn and SHIP-1 are enzymes that are found in blood cells, and both participate in terminating cellular responses. As such, these enzymes are critically important for maintaining stability in the immune system. While these enzymes have unique roles, we also have good evidence that in some instances Lyn and SHIP-1 participate in the same biochemical pathway. We have created mice that are unable to make Lyn protein, and have found that these mice develop blood cell tumours. Mice lacking SHIP-1 develop a number of haematological defects, but die at a young age due to an inflammatory lung condition, making an assessment of the role of SHIP-1 in age-dependent tumour development difficult. We now wish to study the role of SHIP-1 in tumour development, by generating mice that lack SHIP-1 in specific white blood cell compartments. We are also investigating how SHIP-1 and Lyn cooperate in tumour suppression, and we have recently generated mice that simultaneously lack both SHIP-1 and Lyn. Preliminary studies indicate that compound mutant mice develop multiple haematological malignancies. We will fully characterize tumour development in these animals, and determine the molecular basis for this pathology. We will focus on two pathways that have been previously implicated in oncogenesis. These studies will improve our insight into how Lyn and SHIP-1 cooperate in blood cell development, cellular homeostasis and oncogenesis, and add to our biological and biochemical understanding of tumour suppressor networks.Read moreRead less
The Role Of Hox Genes In Myeloid Cell Development And Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$591,286.00
Summary
The transformation of normal white blood cells into leukaemic cells occurs as a result of changes to the genes of those cells. These changes are often characteristic of particular cancers and carry diagnostic and prognostic significance. This work will determine how critical some of the typical genetic changes of leukaemia are to the occurrence and persistence of cancer. Importantly, we will determine whether targeting these changes can provide new and effective approaches to treatment.
The Tumour Cell-specific Nuclear Targeting Properties Of Chicken Anaemia Virus VP-3: Potential For Anti-tumour Therapy
Funder
National Health and Medical Research Council
Funding Amount
$465,210.00
Summary
Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anti-cancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that confers efficient localisation in the nucleus of tumour cells ....Current trends indicate that cancer will cause 40% of all deaths in Australia by 2012, meaning that new anti-cancer strategies are urgently required. Our proposal intends to examine the subcellular targeting abilities of the unique tumour-cell specific agent apoptin (VP3 - viral protein 3), a small protein encoded by the genome of the chicken anaemia virus. Using various strategies, we have identified part of the apoptin molecule that confers efficient localisation in the nucleus of tumour cells, but not non-tumour cells. Our experimental program intends to define this tumour cell-specific targeting signal in detail, and determine the molecular basis of the differential subcellular localisation of apoptin in tumour compared to normal cells. This should contribute fundamental new information regarding the differences between cancer and normal cells. Additionally, we intend to optimise the targeting signal and perform initial experiments to test its efficacy in targeting anti-tumour drugs to the nucleus of tumour cells. Our long-term aim is to use the apoptin tumour cell-specific nuclear targeting signal as part of modular constructs to combat cancer efficiently, and above all, with minimal damage to normal cells and tissues.Read moreRead less