Interaction Of Mc1r With The PRb And P53 Pathways In UVR-induced Melanoma Development
Funder
National Health and Medical Research Council
Funding Amount
$553,479.00
Summary
This project will shed light onto fundamental processes causing UV-induced melanoma (MM). Innate differences between individuals, independent of pigmentation, influence MM development. We will study the mechanisms of UVR-induced MM development in mice carrying gene mutations (Cdk4, Arf, Mc1r) that underpin human MM susceptibility. Knowledge of the sensitivity of an one's MCs to UV could be critical for targeting susceptible groups for health education campaigns and more intense screening.
The Role Of MC1R Polymorphism In Skin Cancer Risk Phenotypes
Funder
National Health and Medical Research Council
Funding Amount
$480,750.00
Summary
Sunsmart campaigns are a unifying element in the lives of many Australians who wish to ensure protection against the damaging effects of ultraviolet rays in sunlight. Indeed, Australians have the highest incidence of UV-induced melanoma in the world. Although it is evident that lighter skin colours are more susceptible to sun damage, the relationship between sun exposure, skin type and melanoma formation is less clear. An essential first step in understanding the complex interactions that give r ....Sunsmart campaigns are a unifying element in the lives of many Australians who wish to ensure protection against the damaging effects of ultraviolet rays in sunlight. Indeed, Australians have the highest incidence of UV-induced melanoma in the world. Although it is evident that lighter skin colours are more susceptible to sun damage, the relationship between sun exposure, skin type and melanoma formation is less clear. An essential first step in understanding the complex interactions that give rise to melanoma, and in identifying individuals that have a high susceptibility, is to reduce phenotypic analyses to genotypic classifications. As pigmentation phenotype is a factor of central importance in determining an individuals risk for melanoma, characterisation of the genes underlying the physical qualities of human eye, hair and skin colour will give a more direct and accurate genotypic assessment of risk. Results from an epidemiology study of melanoma patients in Queensland have identified a number of genetic changes within the melanocyte stimulating hormone receptor (MC1R) gene that associate with skin, hair and eye colour as well as with incidence of melanoma. Further investigation of MC1R gene alleles which segregate with skin and hair colours will provide the beginning for a whole new genotype-based classification of skin colour and melanoma risk, and will significantly contribute to our understanding of what makes some individuals highly susceptible to melanoma while others are not. Indeed, MC1R polymorphisms may numerically be the most important melanoma predisposition gene yet identified, exerting its effects as one of those common genes of small effect which may account for much more of the case load in melanoma than rarer genes of large effect. Studies such as this will enable powerful genotyping methods to be employed in identification of those individuals at highest risk for melanoma and other skin cancers.Read moreRead less
DNA Damage Induced By UVA And UVB In Squamous Cell Carcinoma Progression
Funder
National Health and Medical Research Council
Funding Amount
$65,000.00
Summary
Australia has the highest incidence of skin cancer in the world. This results from immigration of individuals with fair skin to Australia. Skin cancer is three times as common as all other cancers combined. Overall, the incidence of skin cancer continues to rise in Australia and it will be several years before the true effectiveness of preventative programs are known. In the meantime, 1000 Australians die each year from skin cancer. Modern sunscreens, even those with high SPF and labelled as bro ....Australia has the highest incidence of skin cancer in the world. This results from immigration of individuals with fair skin to Australia. Skin cancer is three times as common as all other cancers combined. Overall, the incidence of skin cancer continues to rise in Australia and it will be several years before the true effectiveness of preventative programs are known. In the meantime, 1000 Australians die each year from skin cancer. Modern sunscreens, even those with high SPF and labelled as broad spectrum do not protect very well from UVA, though they are very effective UVB filters. Most sunscreens absorb or reflect only about 50% as much UVA as UVB. Thus sunscreen use alters the spectrum of UV received. This is an important issue, because if sunscreens are used to prolong sun exposure they will selectively increase the amount of UVA reaching the skin, and the sun contains a lot more UVA than UVB. There is only limited evidence to suggest they protect from skin cancer in humans whereas there is good evidence that they protect from precursor lesions. We have developed a new hypothesis, that UVB is primarily responsible for development of preneoplastic lesions (solar keratosis and dysplastic nevi) whereas UVA plays a relatively more important role in their progression to malignancy. This hypothesis would explain why sunscreens are more effective at preventing nevi and solar keratosis formation than they are at preventing melanoma and squamous cell carcinoma. Until the action spectrum defining the wavelengths responsible for skin cancer induction is known, the optimal methods for protection from skin cancer will be difficult if not impossible to design. That different wavelengths may be involved in different phases of skin cancer development in humans is a novel hypothesis: if it is correct it will have profound implications for both the design of sunscreens and our current public health programmes for skin cancer prevention.Read moreRead less
A Novel Tumour Suppressor Function Of E2F7 In Squamous Cell Carcinoma Formation
Funder
National Health and Medical Research Council
Funding Amount
$524,124.00
Summary
squamous cell carcinomas of the skin are the second most common skin cancer. In this proposal we present data showing that a new gene, E2F7, may play an important role in the development of squamous cell carcinoma. If true, these studies will identify a new therapeutic target that could be exploited in developing novel anticancer therapies.
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
Investigation Of The Low Dose UV G2 Phase Checkpoint And Its Potential Exploitation In The Treatment Of Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$35,085.00
Summary
The research aims to indentify the role UV exposure contributes to the development of melanoma and if this knowledge can be used to develop new methods in the prevention and treatment of this disease
Germline Mutations Identified In Melanoma-prone Kindreds Can Impair The Function Of The P14ARF Tumour Suppressor
Funder
National Health and Medical Research Council
Funding Amount
$257,036.00
Summary
Approximately 10% of people in Australia are at high risk of developing melanoma because they carry a faulty gene. Many of these melanoma-prone individuals carry a single mutation that can disrupt two genes, p16INK4a and p14ARF. These genes are both involved in regulating the growth of cells via different pathways. The role of p16INK4a in cancer development is well established and the many functions of this gene are under intense investigation. In contrast, the role of p14ARF in melanoma progres ....Approximately 10% of people in Australia are at high risk of developing melanoma because they carry a faulty gene. Many of these melanoma-prone individuals carry a single mutation that can disrupt two genes, p16INK4a and p14ARF. These genes are both involved in regulating the growth of cells via different pathways. The role of p16INK4a in cancer development is well established and the many functions of this gene are under intense investigation. In contrast, the role of p14ARF in melanoma progression has not been studied. We will be analysing in detail how faulty p14ARF promotes uncontrolled cell growth and cancer development. Our research, will dissect the functions of p14ARF and determine whether p14ARF and p16INK4a co-operate in maintaining normal cell growth. This work is essential to our understanding of melanoma development and will provide clinically useful information regarding the biology of human cancer.Read moreRead less
Melanomas are common cancers arising from the pigment cells of the skin. Sunlight is the principal environmental causal factor for this group of cancers, although there is increasing evidence that the effect of sunlight on the pigment cells is not the same for all people. We aim to answer the question. Does host phenotype predict the response of melanocytes to sunlight and in so doing, contribute information that may assist the development of effective prevention strategies
P14ARF Induces P53-independent Growth Arrest By Modulating The Activities Of The E4F And E2F Transcription Factors
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Cutaneous malignant melanoma is an important public health problem, affecting 1 in 30 Australians at some time in their lives, and the incidence of this disaese is increasing rapidly. Approximately 10% of people in Australia are at high risk of developing melanoma because they carry a faulty gene. Many of these melanoma-prone individuals carry a single mutation that can disrupt two genes, p16INK4a and p14ARF, that are involved in regulating the growth of cells via different pathways. The role of ....Cutaneous malignant melanoma is an important public health problem, affecting 1 in 30 Australians at some time in their lives, and the incidence of this disaese is increasing rapidly. Approximately 10% of people in Australia are at high risk of developing melanoma because they carry a faulty gene. Many of these melanoma-prone individuals carry a single mutation that can disrupt two genes, p16INK4a and p14ARF, that are involved in regulating the growth of cells via different pathways. The role of p16INK4a in maintaining cell cycle control is well understood and the many functions of this gene are under intense investigation. In contrast, the functions of p14ARF in normal cell regulation are not well understood. We will be analysing in detail how p14ARF protects the cell from uncontrolled growth and inhibits cancer development. Our research will dissect the functions of p14ARF and determine the protein partners that co-operate with p14ARF in maintaining normal cell growth. This work is essential to our understanding of normal cell proliferation and melanoma development and will provide clinically useful information regarding the biology of human cancer.Read moreRead less
Targeting Adaptive Mechanisms To Endoplasmic Reticulum Stress In Melanoma
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
Melanoma is a major Australian health problem, but there is no curative treatment once the disease spreads beyond the skin. We will study the role the response of melanoma cells to stress conditions of an organelle called endoplasmic reticulum in determining sensitivity of melanoma to killing induced by therapeutic drugs. If successful, this study will provide much needed new insights into the resistance of melanoma to treatment and point to new treatment approaches against the disease.