Therapeutic Implications Of A Molecular Link Between Survivin And Telomerase Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
A unifying feature of all types of cancer cells is that they are immortal. Our investigations will build upon our recent results that showed the gene survivin is involved in cancer cell immortalisation. We will characterise a molecular link between survivin and the enzyme telomerase, which is central to cancer cell immortality. Furthermore, we will demonstrate the therapeutic potential of turning off both survivin and telomerase as a novel approach to halting the growth of cancer cells.
Detection Of Alternative Lengthening Of Telomeres In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
In each cell, DNA is packaged into units called chromosomes, the ends of which (i.e., telomeres) become slightly shorter every time they are replicated during the production of new cells. Continued cell replication and hence continued telomere shortening eventually results in the inability of cells to replicate themselves any further. Normal cells have mechanisms to slow down, but not completely prevent telomere shortening. The development of a cancer depends on its cells being able to replicate ....In each cell, DNA is packaged into units called chromosomes, the ends of which (i.e., telomeres) become slightly shorter every time they are replicated during the production of new cells. Continued cell replication and hence continued telomere shortening eventually results in the inability of cells to replicate themselves any further. Normal cells have mechanisms to slow down, but not completely prevent telomere shortening. The development of a cancer depends on its cells being able to replicate themselves many times, and therefore they need to find a method to prevent their telomeres shortening. We discovered one such method, called Alternative Lengthening of Telomeres (ALT), that is used by some cancers. It has been shown in principle that cancer cells can be killed by disrupting their ability to prevent telomere shortening. Therefore, in another project we are developing methods needed to find drugs that inhibit ALT. In the meantime, we have found the first evidence that some normal cells have an ALT-like mechanism. Our speculation is that cancer cells are able to dysregulate and subvert this normal mechanism in order to prevent their telomeres from shortening. In this project, we will analyse the ALT-like mechanism in mice, to determine its characteristics, and to determine what tissues use it. This information will provide critically important insights into the ALT mechanism itself, and the likely side effects of drugs that inhibit ALT.Read moreRead less
The Nuclear Growth Hormone Receptor- Its Actions And Mechanism Of Nuclear Translocation
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourog ....We and others have found that cell surface receptors for growth factors such as EGF, FGF and growth hormone can be found in the nucleus of proliferating cells. We have shown that many cancers have elevated nuclear GH receptor including leukemia, breast and colon cancer. If we artificially target the GH receptor to the nucleus, the resulting cells are tumorigenic when injected into immunocompromised mice, rapidly form ing metastasising tumours. To create more effective inhibitors of this tumourogenesis, and to define the physiological roles of nuclear GH receptor, we will define the transport process which carries the receptor to the nucleus and block it. We will also seek to define how the receptor in the nucleus interacts directly with DNA to inhibit programmed cell death. To carry out these projects we will use sophisticated proteomics -mass spectrometry to identify the proteins interacting with the receptor in the transport and gene activation processes. The role of candidates will be tested by preventing their expression or by direct inhibition of their action using drugs or dominant negative versions. These approaches will provide leads to new anti-cancer therapeutics, and therapies for blocking diabetic blindness and kidney failure.Read moreRead less
Patterns Of Care And Quality Of Life In Patients With Pancreatic Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$680,010.00
Summary
Available evidence suggests that care of patients with pancreatic cancer is variable and dependent on a variety of factors such as geographic location, socioeconomic status and hospital volume. Variability in care may influence survival and quality of life of patients. We propose to conduct a comprehensive study of the management of patients with pancreatic cancer in NSW and, in a substudy in QLD, to determine how variation in management affects patient quality of life.
Role Of Endogenous Bcl-2 Family Proteins In Acute Myeloid Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$474,033.00
Summary
Programmed cell death (apoptosis) is crucial for health. Impaired apoptosis can lead to cancer. In blood cancers, mutations that disrupt apoptosis allow cells to survive whilst acquiring additional mutations. Moreover, the mutations prevent most drug treatments for cancer, which act by inducing apoptosis, from working effectively. Our research will investigate the role of apoptosis in tumour development and in sustaining tumour growth. The results will help to identify new cancer therapies.
Studies Of Genetic Predisposition To Develop Serrated Neoplasia In The Colorectum.
Funder
National Health and Medical Research Council
Funding Amount
$308,291.00
Summary
Colorectal Cancer was once believed to develop only from a certain kind of polyp in the colon called the adenoma. However, recently another type of polyp called the hyperplastic polyp was found to also be capable of producing a cancer. In this proposal, we will look at the possibility that the predisposition to form hyperplastic polyps may be inherited in families.
Normal organ development and many disease processes, such as cancer and tissue damage, depend upon formation of new blood vessels. Our research seeks to identify novel factors regulating blood vessel growth. In this context we have examined the role of proteins that mediate communication between cells, called connexins. By increasing our understanding of the factors affecting blood vessel growth we learn how to create novel therapies to enhance the treatment of ischemic disease and cancer.
The Mechanism By Which Apical-basal Polarity Complexes Regulate The Salvador-Warts-Hippo Pathway
Funder
National Health and Medical Research Council
Funding Amount
$540,099.00
Summary
Cancer is a multi-hit process involving the activation of critical signaling pathways leading to increased proliferation, survival and increased invasion-metastasis. We have discovered that a neoplastic tumour suppressor gene, lgl, acts though the Salvador-Warts-Hippo (SWH) tumour suppressor pathway to inhibit cell proliferation and cell survival. Here we use the model organism, Drosophila, and mammalian epithelial cells to determine the mechanism by which Lgl activates the SWH pathway.
The Tumour Suppressor Lgl In The Regulation Of Cell Signaling, Proliferation And Apoptosis
Funder
National Health and Medical Research Council
Funding Amount
$534,871.00
Summary
Cancer is a disease that affects 1-3 people at some point in their lifetime. Therefore, understanding what causes cancer is of major importance to medical science. This proposal focuses on a group of tumour suppressors, Scrib-Dlg-Lgl, which act in a common pathway to regulate cell polarity (cell shape) and proliferation. We have shown that Lgl also regulates cell death. This proposal focuses on understanding the mechanism by which Lgl regulates the cell proliferation and death machinery.
Control Of Salvador-Warts-Hippo Pathway Activity In Drosophila And Mammals
Funder
National Health and Medical Research Council
Funding Amount
$514,048.00
Summary
The primary function of the Salvador-Warts-Hippo (SWH) pathway is to dictate the appropriate size of organs in developing animals. Deregulation of this pathway results in vastly overgrown organs and can lead to the formation of cancer in humans. Our study will provide important insights into how the size of organs are controlled during development by identifying new SWH pathway components. We will also increase understanding of diseases that arise due to aberrant tissue growth, such as cancer.