Identify the DNA Adduct and Associated Metabolic Alterations in Bladder Cancer of Smokers

鉴定吸烟者膀胱癌中的 DNA 加合物和相关代谢改变

• 批准号: 10371068
• 负责人: RANDA A EL-ZEIN
• 金额: $ 37.55万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371068
• 关键词: Age; Aromatic Amines; Aromatic Hydrocarbons; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Biochemical; Biological; Biological Markers; Bladder Neoplasm; Body Fluids; Cancer Patient; Cancer cell line; Carcinogens; Cell Line; Chemoresistance; Clinical; Clinical Management; Cytosine; DNA; DNA Adducts; DNA Damage; DNA Methylation; DNA Repair; DNA Repair Enzymes; DNA analysis; Data; Detection; Disease; Disease-Free Survival; Dose; Early identification; Enzymes; Epidemiology; Exposure to; Generations; Goals; Immunoblot Analysis; Ketones; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Marker; Metabolic Pathway; Metabolism; Methylation; Methyltransferase; Mind; Modeling; Monitor; Muscle; Neoplasm Metastasis; Nicotine; Nitrosamines; Occupational Exposure; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Prognosis; Proteins; Publications; Risk; Risk Assessment; Risk Factors; Role; Sampling; Seminal; Smoke; Smoker; Smoking; Smoking History; Therapeutic; Time; Tissue Microarray; Tissues; Tobacco smoke; Transcript; United States; Urine; Xenobiotic Metabolism; Xenobiotics; Zein; adduct; base; biomarker panel; case control; chemotherapy; cigarette smoke; clinical translation; clinically relevant; cohort; combinatorial; disease phenotype; exposure to cigarette smoke; former smoker; genome integrity; inhibitor; metabolomics; novel; personalized medicine; predictive marker; small molecule; treatment strategy; tumor; tumor metabolism; tumor progression

Project Summary/Abstract Smoking is a major risk factor for bladder cancer (BCa). Patients with current or past history of smoking have a three times higher likelihood of developing BCa. Smoking is also known to have a potential dose-dependent effect on the grade and stage of BCa, with high-dose smokers having more aggressive disease. In addition, smokers with BCa have a higher likelihood of failing chemotherapy. Currently, markers that can stratify smokers based on their risk of developing BCa are lacking. Furthermore, predictive markers for aggressive BCa among high-dose smokers are also lacking. The central goal of this application is to characterize the DNA adducts and biochemical alterations observed in smoking-associated BCa and use this information to develop metabolite-based predictive markers and therapeutic strategies for this deadly disease. Cigarette smoke contains a number of xenobiotic compounds that include arylamines, methylated metabolites, Nicotine- derived nitrosamine ketone (NNK), Benzo[a]pyrene (BaP), nicotine etc which are usually metabolized by the xenobiotic metabolism and excreted in the urine. Our strong preliminary data demonstrates altered DNA adducts and reprogramming of xenobiotic metabolism in BCa smokers. This effect is exaggerated by components of cigarette smoke including nicotine. Using a novel metabolomics approach, we had earlier shown that BCa was associated with a unique metabolic signature. From the patients perspective it is important to be able to measure these markers non-invasively in body fluids like urine. Intriguingly, metabolites are the end products of overall cellular metabolism. These are small molecules that could be easily monitored in body fluids to interrogate disease phenotype in question. Quiet provocatively, our group is being established to utilize metabolites to further monitor tumors. Thus, our current proposal aims to identify DNA adducts and associated metabolites in BCa smokers and use the information to develop markers for early identification of patients who are at risk for developing aggressive bladder cancer. Further will enable clinicians to take an informed decision about more appropriate therapeutic strategies towards personalized medicine.

项目总结/摘要 吸烟是膀胱癌（BCa）的主要危险因素。目前或过去有吸烟史的患者， 患上BCa的可能性高出三倍吸烟也被认为具有潜在的剂量依赖性 对BCa分级和分期的影响，高剂量吸烟者具有更侵袭性的疾病。此外，本发明还提供了一种方法， 患有BCa的吸烟者化疗失败的可能性更高。目前，可以分层的标记 吸烟者根据他们的风险发展BCa缺乏。此外，攻击性的预测标志物 高剂量吸烟者也缺乏BCa。此应用程序的中心目标是表征 在吸烟相关的BCa中观察到的DNA加合物和生化改变，并利用这些信息， 为这种致命疾病开发基于代谢物的预测标志物和治疗策略。香烟 烟雾中含有大量的异生素化合物，包括芳胺、甲基化代谢物、尼古丁- 衍生的亚硝胺酮（NNK），苯并[a]芘（BaP），尼古丁等，通常由 异生物质代谢并经尿液排出。我们强有力的初步数据表明， BCa吸烟者中异生物质代谢的加合物和重编程。这种影响被夸大了， 香烟烟雾的成分，包括尼古丁。使用一种新的代谢组学方法，我们早些时候 表明BCa与独特的代谢特征有关。从患者的角度来看， 重要的是能够在体液如尿液中非侵入性地测量这些标记物。有趣的是， 是整个细胞代谢的最终产物。这些小分子很容易被监测 以询问所讨论的疾病表型。安静地，我们的小组正在建立 利用代谢物来进一步监测肿瘤。因此，我们目前的建议旨在鉴定DNA加合物， BCa吸烟者中的相关代谢物，并使用这些信息开发标记物，用于早期识别 有发展为侵袭性膀胱癌风险的患者。进一步将使临床医生采取一个 为个性化医疗提供更合适的治疗策略。