Prediction Of Clinical Radiosensitivity Caused By Ionising Radiation During Radiotherapy.
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
Around one to five percent of cancer patients suffer from significant side effects in normal tissue exposed to ionizing radiation during radiotherapy. Although radiotherapy is an effective therapy for cancer treatment, the amount of radiation is generally restricted to minimize the incidence of these severe side effects (radiosensitivity). This means that individuals who don't have radiosensitivity are not getting the dose of radiation that would be most beneficial. A major goal of radiation bio ....Around one to five percent of cancer patients suffer from significant side effects in normal tissue exposed to ionizing radiation during radiotherapy. Although radiotherapy is an effective therapy for cancer treatment, the amount of radiation is generally restricted to minimize the incidence of these severe side effects (radiosensitivity). This means that individuals who don't have radiosensitivity are not getting the dose of radiation that would be most beneficial. A major goal of radiation biology research is to develop efficient predictive measures that could identify radiosensitive individuals prior to treatment. This predictive ability would enable the individualisation of radiotherapy radiation doses, which should result in improvement of tumour control rates and a reduction in the incidence of side effects associated with radiotherapy. We aim to understand radiosensitivity at the molecular level using the powerful technology of microarrays. Using microarray technology, thousands of genes can be tested for expression activity simultaneously. We have a unique tissue bank established from many radiosensitive and non-sensitive control radiotherapy patients. The use of microarray technology on samples from this unique tissue bank may enable the gene expression pattern of individuals that display radiosensitivity to be distinguished from the rest of the population. In conjunction, two additional tests will be used to determine who is susceptible to radiosensitive reactions which include assessment of a DNA repair pathway and assessment of the length of the telomeres (Caps on the ends of the chromosomes), both of which have been shown to be involved with radiosensitivy. This experimentation will hopefully lead to the development of a predictive assay for use in the clinic for cancer patients prior to receiving radiotherapy.Read moreRead less
Primary central nervous system (CNS) tumours, arising in the brain and spinal cord, are the leading cause of cancer-related deaths in children less than 15 years of age. Medulloblastomas and other primitive neuroectodermal tumours (PNETs) are the most common form of primary childhood brain tumours, accounting for 25-30% of cases. Despite notable recent advances in our understanding of the molecular genetic basis of malignancies, the pathogenesis of CNS PNETs remains obscure. To address this prob ....Primary central nervous system (CNS) tumours, arising in the brain and spinal cord, are the leading cause of cancer-related deaths in children less than 15 years of age. Medulloblastomas and other primitive neuroectodermal tumours (PNETs) are the most common form of primary childhood brain tumours, accounting for 25-30% of cases. Despite notable recent advances in our understanding of the molecular genetic basis of malignancies, the pathogenesis of CNS PNETs remains obscure. To address this problem, we propose to apply a novel combinatorial approach for the identification of PNET tumour suppressor genes utilising both representational difference analysis (RDA) and microarray expression profiling. Data from this study will help to elucidate the molecular pathways that are compromised in the initiation and growth of PNETs. This information will have direct implications for the development of improved diagnostic and prognostic indicators necessary for the design of more effective therapeutic strategies for the treatment of PNET patients.Read moreRead less
Molecular Markers Of The Progression Of Intestinal Metaplasia To Gastric Cancer
Funder
National Health and Medical Research Council
Funding Amount
$556,618.00
Summary
Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characteri ....Gastric cancer (GC) is the second most common cause of cancer-related death globally. It is a surgically treatable disease that has good prognosis if detected at an early stage. The majority of patients in our community are detected at a late stage, where less than 20% of patients survive 5 years. The majority of GC is preceded by distinct histological stages that follow a progression from gastric mucosal inflammation, intestinal metaplasia (IM) and eventually cancer. These stages are characterised by genetic events that are largely unknown and occur over a period that can take years. It is also evident, especially in countries where GC is not as prevalent, that only a proportion of individuals will eventually develop GC. The long latency from the develpoment of IM and diagnosis of GC offers an opportunity to intervene and study the changes that lead to GC as well as find genes that may predict which individuals will progress. IM is the stage in which intervention is obvious. It is very easily diagnosed, is present for a long time and, for certain individuals, will eventually accumulate enough genetic events that will mandate progression to GC. Targeted screening of these individuals will enable a feasible strategy to find early GC, and avoid costly non-targeted screening. This proposal seeks to find key genetic events responsible for the transition of IM to GC. The first step utilises Affymetrix arrays to detect genes expressed in IM and specifically linked to GC. These candidates will be validated and used to study their role in the progression to GC using a mouse model of GC. This study is designed to find genes responsible for GC that can be used as: 1) a marker of progression in humans that will be used as a tool to stratify individuals into a screening protocol; 2) candidates to be tested in animal studies to study the pathogenesis of GC and potentially used as preventative or therapeutic targets.Read moreRead less
Regulation Of The Quality Of DNA Repair By Timing In The Cell Cycle
Funder
National Health and Medical Research Council
Funding Amount
$468,794.00
Summary
During responses to infection or immunisation, antibody-producing _B� cells mutate their antibody genes at extreme rates. Rare mutations which improve the antibodies are selected by competition between B cells favouring those which make the best antibodies: Darwinian evolution on extreme _fast-forward�. We aim to understand this process because it is essential for normal immunity and effective vaccination, and because when it goes wrong, it can cause aggressive human cancers.
Development Of DNA Targeted Platinum Agents As Potential Anticancer Drugs
Funder
National Health and Medical Research Council
Funding Amount
$410,250.00
Summary
A number of clinically useful anticancer drugs damage DNA. As a result of this damage these drugs kill cancer cells. This project aims to develop new platinum-containing compounds which are specifically targeted to DNA. Through this strategy it is possible that new and more useful anticancer drugs could emerge.
Mechanisms Of Macrophage Activation By Immunostimulatory DNA
Funder
National Health and Medical Research Council
Funding Amount
$230,728.00
Summary
This project is based upon the observation that the mammalian immune system can distinguish between its own genetic material (DNA) and the genes of infectious agents such as bacteria. This fact has implications for understanding how the immune system copes with infection, and also for design of new therapies and vaccines. Our central aim is to define exactly how this recognition system works. The cells that respond most vigorously to foreign DNA are large white blood cells called macrophages. We ....This project is based upon the observation that the mammalian immune system can distinguish between its own genetic material (DNA) and the genes of infectious agents such as bacteria. This fact has implications for understanding how the immune system copes with infection, and also for design of new therapies and vaccines. Our central aim is to define exactly how this recognition system works. The cells that respond most vigorously to foreign DNA are large white blood cells called macrophages. We aim to find the macrophage protein which binds to foreign DNA and triggers the activation of the immune system. The type of immune responses initiated by foreign DNA may be useful in treatment of allergies and cancer and for improving vaccinations.Read moreRead less