Resistant forms of childhood acute lymphoblastic leukaemia (ALL) constitute a leading cause of cancer-related deaths in children. Despite tremendous improvements in therapy, 25-30% of patients still experience a relapse and many of them occur in patients stratified as low risk. Further treatment is often toxic, frequently unsuccessful and carries the risk of significant long-term morbidity. For the design of more appropriate therapy, information on the biology of relapsed ALL is urgently require ....Resistant forms of childhood acute lymphoblastic leukaemia (ALL) constitute a leading cause of cancer-related deaths in children. Despite tremendous improvements in therapy, 25-30% of patients still experience a relapse and many of them occur in patients stratified as low risk. Further treatment is often toxic, frequently unsuccessful and carries the risk of significant long-term morbidity. For the design of more appropriate therapy, information on the biology of relapsed ALL is urgently required. The sequencing of the human genome and advanced screening technology (microarrays) allow the detailed analysis of expression patterns in large numbers of specimens. We propose to study the genetic features of this disease by investigating 28 childhood ALL patients from whom we have stored specimens received at two time points, one at diagnosis and one at relapse. The hypothesis of this study is that relapsed leukaemias display genetic features which are correlated to their resistance to therapy. The specific questions we will be asking are: (1) Which genes are expressed at high levels in leukaemia specimens at the time of relapse while not expressed (or expressed at lower levels) at the time of diagnosis and vice versa? (2) What is the function of differentially expressed genes? (3) Is the pattern of gene expression correlated with resistance to the particular drug therapy used? (4) Is the leukaemia clone at relapse related or unrelated to the clone present at diagnosis, as determined by receptor rearrangement? The expression levels of identified discriminator genes will be confirmed by real-time quantitative polymerase chain reaction (PCR). The quality of this set of specimens makes them particularly suited to achieve the stated goals, providing a unique opportunity to investigate drug resistance in childhood ALL. The data generated will provide the basis for the examination of genes suitable as new therapeutic targets.Read moreRead less
The Role Of IQGAP1 In Human High-Grade Glioma And Its Regulation By MiR-124-A
Funder
National Health and Medical Research Council
Funding Amount
$69,137.00
Summary
Survival rates for many cancers are improving, however, for most patients diagnosed with a high grade glioma (HGG) there is limited long term survival. The treatments administered have limited effectiveness due to extensive infiltration of the tumour cells. New therapeutic strategies targeting the invading cell population to further reduce tumour spread are needed. Hence, a better understanding of the mechanisms promoting glioma migration and invasion are urgently required in this fatal disease.
Investigating Tumour Maintenance Using Regulated RNA Interference
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
Inhibiting gene expression using the recently discovered process known as RNA interference (RNAi) can be used as an experimental tool to analyse specific genes, in cells and genetically engineered animal models of human disease. I propose to validate potential drug targets in cancer by using RNAi to inhibit specific genes in established mouse tumours. A further aim is to use RNAi to mimic human cancer gene mutations in mouse cancer models, to discover novel tumour suppressor genes.
Definition Of The Role Of Senescence In Tumour-associated Endothelial Cells.
Funder
National Health and Medical Research Council
Funding Amount
$583,081.00
Summary
'Cellular senescence' is a mechanism to stop cells growing, and it may protect against tumour growth. However, it may also induce changes in cells leading to 'pro-tumour' effects. We have identified a gene - which we have called SEN1 - which induces senescence in the blood vessels of tumours. This gene may cause alterations in the blood supply to the tumour allowing it to grow and to resist chemotherapy. Understanding this gene may allow us to treat cancer by shutting off its blood supply.
Dissecting The Function Of The Hedgehog-Patched Pathway In Breast Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$606,811.00
Summary
There have been significant improvements in survival from breast cancer, particularly due to specialised treatments that target faulty pathways in the growth of cancer cells. One newly described, aggressive type of breast cancer called basal-like breast cancer lacks specialised treatment. We will determine whether the 'Hedgehog' signalling pathway is a suitable target for basal breast cancer therapy.
The Ability Of Sunscreens To Protect Against The Induction Of Solar Irradiation-induced Melanocytic Naevi In Vivo.
Funder
National Health and Medical Research Council
Funding Amount
$106,854.00
Summary
Melanoma is an increasing problem in Australia. Strong evidence supports the finding that the number of moles on skin is a good indicator of future melanoma risk and a short term marker of adverse reactions to melanoma-inducing sun exposure in humans. While recommendations for sun protection have been proposed for many years, it is currently unknown what component of sunlight induces melanoma or whether sunscreens protect against the formation of melanoma. Using an animal model for human moles o ....Melanoma is an increasing problem in Australia. Strong evidence supports the finding that the number of moles on skin is a good indicator of future melanoma risk and a short term marker of adverse reactions to melanoma-inducing sun exposure in humans. While recommendations for sun protection have been proposed for many years, it is currently unknown what component of sunlight induces melanoma or whether sunscreens protect against the formation of melanoma. Using an animal model for human moles of the skin we aim in contributing to the answers of these two questions .Read moreRead less
Targeting MYC-driven Cancers By Inhibition Of The MTOR Pathway
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
This proposal will evaluate a new strategy for treating cancers associated with the cancer causing gene MYC. Globally there are more than 1 million cases of MYC-associated cancers diagnosed per year. Based on encouraging early results we will test if turning off the proteins associated with mTOR will be an effective strategy for treating MYC cancers using state-of-the-art cancer models and investigate why these cancers respond.
Molecular Mechanisms And Control Of Alternative Lengthening Of Telomeres
Funder
National Health and Medical Research Council
Funding Amount
$453,055.00
Summary
Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell fr ....Studies of a mechanism cancer cells use to protect the ends of their chromosomes The DNA within cell nuclei is arranged in linear packages referred to as chromosomes, capped at each end by structures called telomeres. Telomeres consist of a long stretch of a repetitive DNA sequence that does not contain any genes. Most normal cells are unable to copy the DNA at the extreme ends of their chromosomes, so every time they divide their telomeres get slightly shorter. This ultimately stops the cell from dividing any further, and acts as a very potent barrier to the cell becoming cancerous. Some normal cells are not subject to this inexorable telomere shortening: these are the germ cells in the testis and ovary, that are responsible for passing on genetic material to the next generation. Such cells express an enzyme, telomerase, which is able to synthesise new telomeric DNA to replace that lost during cell division. 85% of human cancers are also able to prevent shortening of their telomeres - and thus have breached the barrier that normally prevents unlimited cell proliferation - via telomerase activity. Therefore, if drugs that inhibit telomerase can be developed they may be a very useful new form of cancer treatment. We have found, however, that some cancers are able to prevent telomere shortening by a process that does not involve telomerase, and which we refer to as Alternative Lengthening of Telomeres (ALT). One practical implication of this finding for the design of new cancer treatments is that telomerase inhibitors will need to be used in combination with ALT inhibitors. In this study, we will determine A. how normal cells keep the ALT mechanism permanently shut down and B. the molecular details of the ALT mechanism itself. An understanding of these processes may ultimately contribute to the development of novel cancer treatments that disrupt the ability of cancer cells to divide an unlimited number of times.Read moreRead less