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：
10829054
负责人：
GYORGY PARAGH
金额：
$ 17.3万
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：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10829054
关键词：
Acceleration Actinic keratosis Acute Adverse effects Aftercare Antioxidants Appearance Area Automobile Driving Biological Markers Biopsy Specimen Cells Chronic Clinical Clinical Research Clinical Trials Clone Cells Clothing Consumption Cream DNA Damage DNA Repair Data Diagnosis Disease Dose Early Intervention Effectiveness Exposure to Female Fluorouracil Frequencies Future Genes Genomics Growth Human Immune response Individual Induced Mutation Lesion Light Mainstreaming Malignant Neoplasms Marketing Measurement Measures Methods Modeling Mus Mutate Mutation Niacinamide Outcome Patient risk Pattern Play Polypodium (plant)Pre-Clinical Model Prevention Prevention strategy Preventive measure Preventive therapy Preventive treatment Primary Prevention Radiation Recommendation Recording of previous events Reporting Risk Risk Factors Risk Reduction Role Sampling Secondary Prevention Skin Skin Cancer Sun Exposure Sunburn Sunscreening Agents Technology Testing Time Treatment Efficacy Tumor Burden Tumor Suppressor Proteins UV carcinogenesis UV induced Ultraviolet Rays Woman Work aggressive therapy cancer care cancer prevention cancer risk carcinogenesis care outcomes cell growth clinical sequencing comparison control computerized tools dietary supplements drinking water efficacy evaluation experience genotoxicity improved insight invention keratinocyte male men mouse model novel oral supplementation photoprotection pre-clinical premalignant prevent prevention effectiveness protective effect sex disparity skin cancer prevention skin damage skin squamous cell carcinoma sun damage sun protection sunlight-induced targeted sequencing treatment response treatment strategy tumor growth tumor initiation tumor progression

项目摘要

Methods are available to prevent cutaneous squamous cell carcinoma (cSCC), the second most common cancer in the US, but are not appropriately used because currently established and mainstream prevention methods (sunscreen, photoprotective clothing) are often impractical and hard to use, and secondary prevention methods like field treatment with 5-fluorouracil cream, have numerous adverse effects. Therefore, less toxic and efficacious prevention methods are sorely needed. Several oral supplements are excellent candidates for primary and secondary prevention of cSCC. However, methods to evaluate their effectiveness in early photocarcinogenesis in a timely and financially feasible manner are lacking. Therefore, we lack data to drive their broader adaptation and predict their long-termefficacyfor human use. Ultraviolet light (UV) fromthe sun induces genomic damage, which is the primary cause of skin cancer. Early during carcinogenesis, UV radiation causes mutations in cells, resulting in the appearance of clusters of mutated cell clones, which later give rise to clinically apparent precancers and, ultimately, skin cancers. We call the mutations driving the growth of these cell groups clonogenic mutations (CMs). CMs are early changes during cSCC formation that appear decades before clinically detectable cancers. Based on previous evidence, CMs may indicate skin cancer risk and evaluate the efficacy of preventative treatment strategies and sun protection. CMs are present in low abundance in the skin, which makes them challenging to detect. However, recent advances in genomic sequencing technology and computational tools allow accurate identification and quantitation of CMs in the skin. We have shown that CMs can be accurately detected and used to evaluate sun-damaged skin areas and that CMs change during clinical secondary preventative therapy. The central hypothesis for this application is that CMs are biomarkers of sun- induced skin damage and that CMs can measure how well dietary supplements work as a preventative therapy. In the first set of studies, we will use Polypodium Leucotomos extract (PLE) and nicotinamide (NAM) as primary prevention agents to evaluate their effectiveness during UV exposure to reduce CMs and delay tumor initiation in a preclinical model. In the second set of studies, we will test NAM as a secondary prevention agent following UV exposure, which is known to induce cSCC. These studies will change how we evaluate a patient’s risk of developing skin cancer, determine the effect of early and easy-to-use skin cancer prevention, and provide crucial preliminary data for future clinical studies to establish the true efficacy of PLE, NAM, and other oral supplements on skin cancer risk reduction. These studies have the potential to shift the focus from treating skin cancer to preventing the occurrence of skin cancer, by improving prevention strategies and cancer care outcomes, and ultimately improving the lives of individuals with a history of sun damage and precancerous lesions. This work focuses on skin cancer; however, as CMs play a crucial first step in cancer growth in most human cancers the framework of this study will have implications for the broader field of cancer prevention.

可以预防皮肤鳞状细胞癌（CSCC）的方法，这是第二常见的癌症在美国，但没有适当使用，因为当前建立和主流预防方法（防晒霜，光保护服）通常不切实际且难以使用，次要预防方法像5-氟尿嘧啶奶油的现场治疗一样，也会产生许多不利影响。因此，毒性较小，迫切需要有效的预防方法。几种口服补充剂是极好的候选人 CSCC的初级和次要预防。但是，评估其早期有效性的方法缺乏及时且在财务上可行的方式的光钙局发生。因此，我们缺乏推动他们的数据更广泛的适应和预测其长期效率化的人类使用。太阳影响的紫外线（UV）基因组损伤，这是皮肤癌的主要原因。癌变的早期，紫外线辐射原因细胞中的突变，导致突变细胞克隆的簇出现，后来引起临床显而易见的挑选者，最终是皮肤癌。我们称之为推动这些细胞组生长的突变克隆发生突变（CMS）。 CM是CSCC编队期间出现数十年的早期变化临床可检测的癌症。根据以前的证据，CMS可能表明皮肤癌风险并评估 CM在皮肤中的丰度低，这使他们挑战检测。但是，基因组测序技术的最新进展和计算工具可以准确识别和定量皮肤中的CMS。我们已经证明了CMS 可以准确检测并用于评估阳光损伤的皮肤区域，并且CM在临床期间发生变化次要预防疗法。该应用的中心假设是CMS是太阳的生物标志物诱发皮肤损伤，CM可以测量饮食补充剂作为预防疗法的工作状况。在第一组研究中，我们将使用白细胞群提取物（PLE）和烟酰胺（NAM）作为主要预防剂评估其在紫外线暴露期间的有效性以减少CMS并延迟肿瘤的启动在临床前模型中。在第二组研究中，我们将测试NAM作为次要预防剂之后紫外线暴露，已知会诱导CSCC。这些研究将改变我们评估患者的风险患皮肤癌，确定早期和易于使用的皮肤癌的影响，并提供至关重要的未来临床研究的初步数据，以确定PLE，NAM和其他口服补充剂的真正效率关于皮肤癌的风险降低。这些研究有可能将重点从治疗皮肤癌转移到通过改善预防策略和癌症护理结果以及最终改善了具有太阳损害和癌前病变历史的个人的生活。这项工作专注于皮肤癌；但是，随着CMS在大多数人类癌症的癌症生长中起着至关重要的第一步这项研究的框架将对癌症预防的更广泛领域具有影响。