The Distinctive Roles Of Tissue Transglutaminase Isoforms In Neuroblastoma
Funder
National Health and Medical Research Council
Funding Amount
$311,567.00
Summary
Neuroblastoma is the commonest solid tumour in early childhood. Neuroblastoma caused by N-Myc oncogene accounts for about one third of the disease and represents a more aggressive subtype with a worse clinical outcome. This project aims to identify factors responsible for N-Myc-induced neuroblastoma initiation and factors sensitizing neuroblastoma cells to anti-cancer drugs, and to provide the basis for clinical trials of a combination therapy in children with neuroblastoma.
Targeting Histone Deacetylases For The Therapy Of Myc-induced Malignancies
Funder
National Health and Medical Research Council
Funding Amount
$356,513.00
Summary
Neuroblastoma is the commonest solid tumour in early childhood. Pancreatic cancer is the fourth leading cause of cancer death in adults. In this application, we will define how proteins called histone deacetylases promote cancer initiation and progression, and whether combination therapy with an inhibitor of the histone deacetylases and another anti-cancer agent exert efficient synergistic anti-cancer effects in animal models of neuroblastoma and pancreatic cancer.
The Interferon Inducible Transcription Factor IFI 16.
Funder
National Health and Medical Research Council
Funding Amount
$151,208.00
Summary
Interferons (IFNs) play an important role in human biology by regulating cell growth and differentiation, immune function and inhibiting viral replication. These vital functions of type I (alpha and beta) and type II (gamma) IFN are triggered upon binding of IFN to their cognate cell surface receptors. This initiates a series of intracellular signalling cascades resulting in the activation of key transcription factors which induce the expression of specific cellular target genes. The protein pro ....Interferons (IFNs) play an important role in human biology by regulating cell growth and differentiation, immune function and inhibiting viral replication. These vital functions of type I (alpha and beta) and type II (gamma) IFN are triggered upon binding of IFN to their cognate cell surface receptors. This initiates a series of intracellular signalling cascades resulting in the activation of key transcription factors which induce the expression of specific cellular target genes. The protein products of these genes in turn directly or indirectly mediate the necessary biological response to maintain cellular homeostasis. While there are hundreds of cellular genes that are induced following IFN stimulation, the molecular and biological functions of the protein products of many of these genes are often not known. IFI 16 is one such IFN-induced gene that belongs to a family of related genes found in human and mouse. Little is known about what role IFI 16 may play in an IFN response and how it may function to mediate its effect. The proposed study is aimed at understanding how IFI 16 is upregulated following treatment of cells with IFN, identifying which cellular genes may be directly regulated by IFI 16 and how this happens, and whether IFI 16 plays a role in the development of specific blood cells.Read moreRead less
Role Of Immediate Early Gene Induction And AP-1 Activation In HDAC Inhibitor Induced Apoptosis.
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Histone deacetylase inhibitors (HDACi) are a novel class of anti-tumor agents, recently approved for the treatment of cutaneous T-cell lymphoma. The goal of this study is to improve our understanding of how this class of drug induces tumor cell death. These studies are designed to provide insight into which patients are most likely to benefit from treatment with these agents. Second, they will provide direction into how the therapeutic efficacy of HDACi may be enhanced, through combination with ....Histone deacetylase inhibitors (HDACi) are a novel class of anti-tumor agents, recently approved for the treatment of cutaneous T-cell lymphoma. The goal of this study is to improve our understanding of how this class of drug induces tumor cell death. These studies are designed to provide insight into which patients are most likely to benefit from treatment with these agents. Second, they will provide direction into how the therapeutic efficacy of HDACi may be enhanced, through combination with other existing therapeutics.Read moreRead less
The Organisation Of The Chromosome Into Distinct Epigenetic Domains And Its Link With Development And Disease
Funder
National Health and Medical Research Council
Funding Amount
$521,591.00
Summary
This investigation will show that a key cellular mechanism that determines how the chromosome is organised into stable domains is by changing the make-up of chromosomal domains through the replacement of histone proteins with specialised forms of histones called variants . This fundamental research will provide important new information on how chromosomes become unstable in cancer.
Targeting Histone Deacetylases To Overcome Resistance Of BRAFV600E Melanoma Cells To Apoptosis
Funder
National Health and Medical Research Council
Funding Amount
$353,140.00
Summary
Results from early clinical studies with a new class of drugs in the treatment of melanoma have been very encouraging, but most tumors initially respond to the drugs regrow after short periods. We have recently shown that this is mainly related to resistance of melanoma cells to cell death induced by the drugs. In this project, we aim to explore a novel approach to overcome this resistance. If successful, the results will lead to new approaches in the treatment of melanoma.
Defining The Apoptotic And Therapeutic Activities Of Histone Deacetylase Inhibitors.
Funder
National Health and Medical Research Council
Funding Amount
$526,878.00
Summary
HDAC inhibitors (HDACi) are new chemotherapeutic drugs that kill tumors cells through a cell suicide process called apoptosis. We have now established a mouse model of human lymphoma whereby pro-apoptotic proteins have been eliminated or anti-apoptotic proteins overexpressed. We will identify the apoptotic proteins and pathways that are necessary for HDACi to kill cancer cells. Such information will lead to a more targeted or rational approach to chemotherapy using HDACi.
Regulation Of The Histone Code By Histone Variants
Funder
National Health and Medical Research Council
Funding Amount
$589,425.00
Summary
A fundamental unanswered question in biology is how a single fertilized mammalian cell can differentiate into a multicellular organism when every differentiated cell type inherits the same DNA. Fundamental to this development process is that different sets of genes are expressed in different cell types. This investigation will show that a key mechanism to regulate gene expression is the way our DNA is covered with specifically modified and altered forms of histone proteins.
The mechanisms controlling cell growth are often disrupted in cancers. We have identified on such growth control mechanism. When normal body cells are treated with a particular family of drugs known as histone deacetylase inhibitors, they react by stopping proliferating, but will resume normal growth when the drug is removed. However, we have found that similarly treated tumour cells are killed by these drugs. The difference between the normal and tumour cells is the functionality of a particula ....The mechanisms controlling cell growth are often disrupted in cancers. We have identified on such growth control mechanism. When normal body cells are treated with a particular family of drugs known as histone deacetylase inhibitors, they react by stopping proliferating, but will resume normal growth when the drug is removed. However, we have found that similarly treated tumour cells are killed by these drugs. The difference between the normal and tumour cells is the functionality of a particular growth control. The identification of how this growth control mechanism operates in normal cells, and defining the defect in tumour cells has the potential to identify new targets for more specific and potent anti-cancer drugs. The increased specificity, i.e. destruction of only the tumour cells while have little or no effect on the surround normal body tissue, would be extremely beneficial as one of the drawbacks to conventional anti-cancer treatments is their unwanted normal tissue toxicities. This is cause of the many debilitating side effects associated with chemo and radiotherapy which can limit the clinical effectiveness of these treatments.Read moreRead less
Antiviral therapy for HIV infection has substantially reduced mortality but HIV can't be cured. This is because HIV causes a silent or latent infection in some cells. This grant will investigate a new class of drugs which show promise in reversing latent infection and potentially eliminating HIV from infected patients