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.

有多种方法可预防第二常见癌症——皮肤鳞状细胞癌 (cSCC) 在美国，但由于目前已建立的主流预防方法而未得到适当使用（防晒霜、光防护服）往往不切实际且难以使用，二级预防方法与现场治疗用5-氟尿嘧啶乳膏一样，有许多不良反应，因此毒性较小。迫切需要有效的预防方法，几种口服补充剂是很好的选择。然而，早期评估其有效性的方法。因此，我们缺乏及时且经济上可行的方式进行光致癌研究，因此我们缺乏数据来推动其发展。更广泛的适应性并预测其对人类使用的长期功效。基因组损伤是皮肤癌早期的主要原因，紫外线辐射会导致这种损伤。细胞突变，导致出现突变细胞克隆簇，随后引起临床明显的癌前病变，最终形成皮肤癌，我们将这些突变称为驱动这些细胞群生长的突变。克隆突变 (CM) 是 cSCC 形成过程中的早期变化，早在几十年前就出现了。根据临床可检测的癌症，CM 可以指示皮肤癌风险并评估皮肤癌的风险。预防性治疗策略和防晒措施的功效在皮肤中含量较低，然而，基因组测序技术和技术的最新进展使得它们难以检测。计算工具可以准确识别和定量皮肤中的 CM。可以准确检测并用于评估晒伤皮肤区域以及临床过程中 CM 的变化该应用的中心假设是 CM 是阳光的生物标志物。引起的皮肤损伤，CM 可以测量膳食补充剂作为预防疗法的效果。在第一组研究中，我们将使用水龙骨提取物 (PLE) 和烟酰胺 (NAM) 作为主要原料预防剂评估其在紫外线照射期间减少 CM 和延迟肿瘤发生的有效性在临床前模型中，我们将测试 NAM 作为二级预防剂的效果。众所周知，紫外线照射会诱发鳞状细胞癌，这些研究将改变我们评估患者罹患鳞状细胞癌的风险的方式。发展皮肤癌，确定早期且易于使用的皮肤癌预防的效果，并提供关键的为未来临床研究确定 PLE、NAM 和其他口服补充剂的真实功效提供初步数据这些研究有可能将重点从治疗皮肤癌转向。通过改善预防策略和癌症护理结果来预防皮肤癌的发生，以及这项工作最终改善了有阳光损伤和癌前病变史的人的生活。重点关注皮肤癌；然而，由于 CM 在大多数人类癌症中发挥着至关重要的第一步这项研究的框架将对更广泛的癌症预防领域产生影响。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

HotSPOT: A Computational Tool to Design Targeted Sequencing Panels to Assess Early Photocarcinogenesis.

HotSPOT：一种设计靶向测序面板以评估早期光癌发生的计算工具。

DOI：
发表时间：
2023-03-05
期刊：
影响因子：
5.2
作者：
Grant, Sydney R;Rosario, Spencer R;Patentreger, Andrew D;Shary, Nico;Fitzgerald, Megan E;Singh, Prashant K;Foster, Barbara A;Huss, Wendy J;Wei, Lei;Paragh, Gyorgy
通讯作者：
Paragh, Gyorgy