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：
10339333
负责人：
GYORGY PARAGH
金额：
$ 64.76万
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/10339333
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 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 The Sun Time Training UV Radiation Exposure UV carcinogenesis UV induced UV protection UV sensitive UVB induced Ultraviolet B Radiation Ultraviolet Rays Validation Work aged base 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 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 targeted sequencing therapy design treatment response treatment strategy tumor

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 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 The Sun Time Training UV Radiation Exposure UV carcinogenesis UV induced UV protection UV sensitive UVB induced Ultraviolet B Radiation Ultraviolet Rays Validation Work aged base 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 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 targeted sequencing therapy design treatment response treatment strategy tumor

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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.

1平方细胞皮肤癌（SCC）是美国第二常见的癌症。有可用的方法 2防止SCC但不适当使用，因为我们缺乏评估它们在A中的有效性的方法 3个及时的方式。太阳的紫外线（UV）诱导基因组损害，这是最重要的原因 4个皮肤癌。在癌症形成过程的早期，紫外线引起细胞中的突变，导致小 5个克隆，突变细胞的簇。导致这些克隆生长的早期突变称为 6个克隆发生突变（CM）。 CM是SCC组中的早期变化 7临床可检测的癌症。基于以前的证据，CMS可能会向皮肤癌的风险发出信号并评估 8预防治疗策略和防晒的有效性。 CM在皮肤中的丰度低 9使他们挑战检测。但是，基因组测序技术的最新进展和 10计算工具可以准确识别和定量皮肤中的CMS。初步数据已显示 11可以准确检测到CMS，并用于评估太阳损伤皮肤区域。发现的许多CM 12正常的阳光暴露的皮肤在SCC中也很常见。该应用程序的中心假设是CM是 13个阳光引起皮肤损伤的生物标志物，CM可以测量皮肤癌的策略如何 14预防和预防治疗工作。在第一组研究中，我们将完善先前开发的 15太阳面板通过鉴定阳光暴露与非阳性裸露的皮肤中最常见的CMS诱导CM。 16随后的研究将研究紫外线暴露对CM面板变化的影响和开发 17皮肤癌。这些研究将评估CMS的模式和患皮肤癌的风险。接下来， 18精制面板CMS将用于检查旨在预防皮肤癌严重的治疗方法 19阳光受损的皮肤区域减少了CM和皮肤癌的形成。在最后一组研究中，CMS将用于 20评估防晒策略的效率，例如防晒霜。太阳保护因子（SPF）广泛 21用于评估防晒霜。但是，SPF测量皮肤发红的减少而不是实际 22 DNA损伤。基因组DNA损伤会导致皮肤癌，而不是皮肤中的“发红”。基因组损伤 23可能是由长期的太阳破坏引起的，不会引起晒伤。在最后一组研究中，使用了CMS 24评估防晒霜以防止基因组损伤和皮肤癌的有效性。这些研究 25将改变我们评估患者患皮肤癌风险的方式以及我们如何确定皮肤的影响 26预防癌症。这些研究有可能将重点从治疗癌症转变为防止 27发生皮肤癌。这将导致癌症护理结果的改善，改善治疗 28策略，并最终具有阳光损害和癌前病变的历史的个人生活。 29这项工作的重点是皮肤癌，但由于CMS在大多数人类癌症中起着至关重要的第一步 30我们的发现和这项研究的框架将对更广泛的预防肿瘤学领域产生影响。