This proposal will focus on determining the effect that disruption of molecules involved in repairing DNA has on development of adverse reactions following cancer radiation treatment. Radiation is efective for cancer but tissues that reside next to the tumour are also exposed to radiation (which can damage DNA) during radiotherapy. About 1-5% of radiotherapy patients develop unexpectedly severe side effects in their normal tissues. The dose of radiation used for treatment to the rest of patients ....This proposal will focus on determining the effect that disruption of molecules involved in repairing DNA has on development of adverse reactions following cancer radiation treatment. Radiation is efective for cancer but tissues that reside next to the tumour are also exposed to radiation (which can damage DNA) during radiotherapy. About 1-5% of radiotherapy patients develop unexpectedly severe side effects in their normal tissues. The dose of radiation used for treatment to the rest of patients (>95%) is restrained to assure only a small proportion risk developing severe reactions. If one could predict which individuals were more susceptible to these reactions, then their large dose could be lowered to avoid the problem, and importantly, the dose could be increased for the majority of the patients, which would lead to a higher cancer cure rate. There are over 130 genes involved in repairing DNA. We hypothesize that dysfunctional DNA repair molecules are likely candidates to cause radiosensitivity in these individuals. In fact, a few of these genes have already been found to cause radiosensitivity, but we aim to assess all of the DNA repair genes in samples from patients that have had severe reactions to radiotherapy. Here we will use biospecimens, unique to our study and obtained from clinically radiosensitive cancer patients. We will use very sensitive, state-of-the-art procedures to test RNA and protein levels in our patients' cells and the latest technology to test what happens when candidate DNA repair molecule levels are altered. Additionally, we will determine the changes in DNA repair molecule numbers in response to different doses of radiation. We anticipate that results from these experiments will lead to the development of a clinical assay to test the likelihood of an individual having a severe reaction to radiotherapy, thus allowing individualization of treatment and, reducing radiotherapy side effects ultimately increasing cancer cure rates.Read moreRead less
Analysis Of Low Radiation Dose Outside Of The Treatment Field Received By Cancer Patients Undergoing Radiotherapy
Funder
National Health and Medical Research Council
Funding Amount
$332,384.00
Summary
Every medical intervention is associated with risk. The present proposal aims to quantify the dose from radiation that is delivered outside the actual target region in radiotherapy of breast cancer patients. This information can help the development of better irradiation techniques as well as inform patients and their carers about possible long term side effects. Finally, the research can be used to finetune radiobiological models by comparing clinical outcomes and accurately calculated doses.
Phase III Trial Of Radical Chemo-radiation Vs Radiation Alone In The Management Of Localised Bladder TCC.
Funder
National Health and Medical Research Council
Funding Amount
$194,875.00
Summary
This trial aims to see if the combination of Chemotherapy and Radiation treatment is indeed superior in eradicating the tumor and preserving the Bladder in a greater number of patients as compared to Radiation treatment alone. If the final results from this study do show chemoradiotherapy to be significantly superior to radiation alone, without an increase in morbidity ( especially long term side effects ) , this may lay the platform for a greater proportion of patients with localised bladder ca ....This trial aims to see if the combination of Chemotherapy and Radiation treatment is indeed superior in eradicating the tumor and preserving the Bladder in a greater number of patients as compared to Radiation treatment alone. If the final results from this study do show chemoradiotherapy to be significantly superior to radiation alone, without an increase in morbidity ( especially long term side effects ) , this may lay the platform for a greater proportion of patients with localised bladder cancer, being in the first instance considered for this organ( bladder) preserving approach something which has become a reality at a number of other sites of cancer with the use of multimodality treatment.Read moreRead less
Ultraviolet-induced Effector Molecules In Ocular Surface Diseases: Regulation Of Expression In Vitro And In Vivo
Funder
National Health and Medical Research Council
Funding Amount
$293,500.00
Summary
Pterygium is a common, recurrent, inflammatory, and sight-threatening complication of the human eye. The disease is characterised by a fleshy vascular growth that gradually covers the ocular surface if left untreated. Limbal dysplasia is a less common disease but in some regards this disease behaves much like a pterygium. We have generated considerable laboratory based data that these ocular surface disorders may be triggered by ultraviolet (UV) radiation and this fits well with the extensive ep ....Pterygium is a common, recurrent, inflammatory, and sight-threatening complication of the human eye. The disease is characterised by a fleshy vascular growth that gradually covers the ocular surface if left untreated. Limbal dysplasia is a less common disease but in some regards this disease behaves much like a pterygium. We have generated considerable laboratory based data that these ocular surface disorders may be triggered by ultraviolet (UV) radiation and this fits well with the extensive epidemiological evidence. To data the only form of treatment is surgical intervention, often with adjunctive topical agents that can cause other more severe complication of the eye. The aim of this investigation is to determine the effectiveness of agents such as retinoic acid and interferons to block or inhibit the down-stream effects of UV radiation. Currently, we have preliminary data that suggests these agents can significantly reduce several molecules that are activated by UV in cultured ocular surface cells. Furthermore, we have clinical evidence that retinoic acid and interferon can resolve both pterygia and conjunctival dysplasia in a small group of patients. If successful, these agents may replace costly and time-consuming surgical approach to treatment.Read moreRead less
CONTINUING MECHANISTIC STUDIES OF UVA PHOTOIMMUNOPROTECTION
Funder
National Health and Medical Research Council
Funding Amount
$261,113.00
Summary
The UVB portion of sunlight causes sunburn, tanning, skin cancer, and suppresses immune function. Longer wavelength UVA is significantly less damaging, may contribute to photoageing and damage to deeper skin layers, but has been much less well studied. UVB-induced immunosuppression appears to be a prerequisite for skin cancer, and experimental protection from the immunosuppression results also in reduced severity of the long-term skin cancer outcome. We have identified a protective effect by UVA ....The UVB portion of sunlight causes sunburn, tanning, skin cancer, and suppresses immune function. Longer wavelength UVA is significantly less damaging, may contribute to photoageing and damage to deeper skin layers, but has been much less well studied. UVB-induced immunosuppression appears to be a prerequisite for skin cancer, and experimental protection from the immunosuppression results also in reduced severity of the long-term skin cancer outcome. We have identified a protective effect by UVA radiation against UVB-immunosuppression when UVA is administered to mice at non-burning environmentally relevant doses. This was an important and unprecedented finding, and is supported by recent observations also in humans. The aim of the present study is to clarify the mechanisms by which this resistance to UVB-induced immunosuppression is achieved, according to 2 main hypotheses: 1. UVA interferes with the actions of cis-urocanic acid, a natural epidermal UV-photoproduct that appears to initiate the immunosuppression by interacting with histamine. 2. UVA alters the balance of immunological control and thus activates normal antioxidant defences of the skin such as metallothionein and haem oxygenase, which antagonise the apparent oxidative requirement for UVB-immunosuppression. These pathways lead to the prediction that increasing the UVA component of the incident radiation will reduce skin cancer development. Humans typically receive disproportionately large UVA doses sunbathing through a UVB-sunscreen, or in cosmetic sunparlours. The assumption that UVA contributes to UVB skin damage may not be true at moderate UV doses, and a potential for UVA to protect from UVB-suppressed immunity and risk of skin cancer would suggest that broad spectrum sunscreens are contraindicated, and that the UVA effects need to be exploited.Read moreRead less
Effect Of Ultraviolet Radiation On Development Of Effector And Memory T Cells To Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$498,328.00
Summary
Australia has the highest incidence of skin cancer in the world, due to our lifestyle that involves high levels of exposure to sunlight. Skin cancer, including melanoma can be destroyed by the immune system, but sunlight inhibits immunity, enabling skin tumours to grow. Our aim is to determine how sunlight affects the activation of effector anti-melanoma T cells, and their development into memory T cells, and the dose of sunlight required to have this effect. It is unknown whether ultraviolet ra ....Australia has the highest incidence of skin cancer in the world, due to our lifestyle that involves high levels of exposure to sunlight. Skin cancer, including melanoma can be destroyed by the immune system, but sunlight inhibits immunity, enabling skin tumours to grow. Our aim is to determine how sunlight affects the activation of effector anti-melanoma T cells, and their development into memory T cells, and the dose of sunlight required to have this effect. It is unknown whether ultraviolet radiation in sunlight suppresses the activation of effector cells that mediate rejection of skin tumours, or their development into memory cells, or migration of activated-memory lymphocytes into skin tumours. The number of antigen reactive T cells is a key issue for tumour immunity and the aim of many clinical immunotherapy trials is to boost these to levels that can effectively destroy the tumour. It is important to establish whether low doses of sunlight readily achievable during normal living, or only higher exposures received when sunbaking, inhibit the number of these effector T cells, and their migration into skin tumours. It is important to determine whether there is a relatively safe threshold level of sunlight exposure to be able to give better advice on sunlight doses that can be achieved without causing serious deleterious health effects. Also these levels of sunlight may interfere with immunotherapy trials and therefore need to be determined. An additional outcome will be to determine whether chemopreventative agents that enhance recovery from sunlight induced suppression of skin allergies are also protective for anti-tumour immunity. The establishment of procedures for prevention of suppression of anti-tumour immunity may enhance the number of T cells activated by natural immunity or during immunotherapy, thereby improving immune rejection of melanoma.Read moreRead less