Advancing skin cancer prevention by tackling UV-induced clonogenic mutations

通过应对紫外线诱导的克隆突变来促进皮肤癌的预防

基本信息

批准号：
10563186
负责人：
GYORGY PARAGH
金额：
$ 59.31万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-02-03 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10563186
关键词：
Adherence Affect Anatomy Area Autopsy Biological Markers Cancer Patient Cells Chronic Clinic Clinical Clinical Trials DNA DNA Damage Data Data Set Detection Development Diagnosis Effectiveness Epidermis Erythema Evolution Feedback Future Genes Genomic DNA Genomic Segment Genomics Growth Human Individual Intervention Kinetics Knowledge Lesion Life Malignant Neoplasms Measurement Measures Methods Modeling Mus Mutagenesis Mutate Mutation NOTCH1 gene Normal tissue morphology Oncology Patient risk Patients Pattern Photography Play Prevention Prevention approach Prevention strategy Preventive measure Preventive treatment Process Recording of previous events Redness Resolution Risk Role Sampling Signal Transduction Skin Skin Cancer Skin Squamous Cell Somatic Mutation Sun Exposure Sun protection factor Sunburn Sunscreening Agents TP53 gene Technology Testing Textiles Time Training UV carcinogenesis UV induced UVB induced Ultraviolet B Radiation Ultraviolet Rays Validation Work aged biomarker identification biomarker panel cancer care cancer prevention cancer risk care outcomes clinically relevant cohort computerized tools dosage effectiveness evaluation efficacy evaluation genetic variant genotoxicity high dimensionality improved indexing irradiation machine learning model mouse model photoprotection pre-clinical predictive panel premalignant prevent research clinical testing skin cancer prevention skin damage skin squamous cell carcinoma standard of care sun damage sun protection sunlight-induced targeted sequencing therapy design treatment response treatment strategy tumor

项目摘要

1 Squamous cell skin cancer (SCC) is the second most common cancer in the US. There are methods available 2 to prevent SCC but are not appropriately used because we lack methods of evaluating their effectiveness in a 3 timely manner. Ultraviolet light (UV) from the sun induces genomic damage which is the most important cause 4 of skin cancer. Early in the process of cancer formation UV causes mutations in cells which result in small 5 clones, clusters of mutated cells. The early mutations that result in the growth of these clones are called 6 clonogenic mutations (CM). CMs are early changes during SCC formation, which appear decades before 7 clinically detectable cancer. Based on previous evidence CMs may signal skin cancer risk and evaluate the 8 efficacy of preventative treatment strategies and sun protection. CM are in low abundance in the skin which 9 make them challenging to detect. However, recent advances in genomic sequencing technology and 10 computational tools allow accurate identification and quantitation of CMs in the skin. Preliminary data has shown 11 that CMS can be accurately detected and used to evaluate sun damaged skin areas. Many of the CMs found in 12 normal sun exposed skin are also common in SCC. The central hypothesis for this application is that CMs are 13 biomarkers of sun induced skin damaged and that CMs can measure how well strategies for skin cancer 14 prevention and preventative treatment work. In the first set of studies we will refine the previously developed 15 panel of sun induced CMs by identifying the most common CMs in sun exposed versus non-sun exposed skin. 16 Subsequent studies will examine the impact of UV exposure on changes in the CM panel and development of 17 skin cancer. These studies will evaluate patterns of CMs and the risk of developing skin cancer. Next, the 18 refined panel of CMs will be used to examine how well treatments designed to prevent skin cancer in heavily 19 sun damaged skin areas reduce CMs and skin cancer formation. In the final set of studies, CMs will be used to 20 evaluate the efficacy of sun protection strategies, such as sunscreens. Sun protection factor (SPF) is widely 21 used to evaluate sunscreens. However, SPF measures reduction in redness of the skin instead of the actual 22 DNA damage. Genomic DNA damage contributes to skin cancer, not “redness” in the skin. Genomic damage 23 can be caused by long term sun damage that does not cause a sunburn. In the final set of studies, CMs are used 24 to evaluate the effectiveness of sunscreens to protect against genomic damage and skin cancer. These studies 25 will change how we evaluate a patient’s risk of developing skin cancer and how we determine the effect of skin 26 cancer prevention. These studies have the potential to shift the focus from treating cancer to preventing the 27 occurrence of skin cancer. This would result in an improvement in cancer care outcomes, improve treatment 28 strategies and ultimately improve the life of individual with a history of sun damage and pre-cancerous lesions. 29 This work focuses on skin cancer but as CMs play a crucial first step in cancer growth in most human cancers 30 our findings and the framework of this study will have implications for the wider field of preventative oncology.