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: 9895423
• 负责人: RANDA A EL-ZEIN
• 金额: $ 39.11万
• 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 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895423
• 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; 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; Proteins; Publications; Resistance; 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; genome integrity; inhibitor/antagonist; metabolomics; novel; outcome forecast; 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.

项目摘要/摘要 吸烟是膀胱癌（BCA）的主要危险因素。当前或过去吸烟史的患者有 发展BCA的可能性高三倍。众所周知，吸烟具有潜在的剂量依赖性 对BCA的等级和阶段的影响，高剂量吸烟者患有更具侵略性的疾病。此外， BCA的吸烟者的化学疗法失败的可能性更高。目前，可以分层的标记 吸烟者基于其发展BCA的风险。此外，积极的预测标记 大剂量吸烟者中的BCA也缺乏。此应用程序的核心目标是表征 在吸烟相关的BCA中观察到的DNA加合物和生化改变，并将这些信息用于 为这种致命疾病开发基于代谢物的预测标记和治疗策略。卷烟 烟雾含有许多异生元化合物，包括芳基胺，甲基化的代谢产物，尼古丁 - 衍生的亚硝胺酮（NNK），苯并[a] pyrene（BAP），尼古丁等，通常由 异生物代谢，并在尿液中排出。我们强大的初步数据表明DNA改变了 BCA吸烟者中异生物代谢的加合物和重编程。这种效果被夸大了 香烟烟的成分，包括尼古丁。使用新型的代谢组学方法，我们较早 表明BCA与独特的代谢特征有关。从患者的角度来看 能够在尿液等体液中非侵入性测量这些标记很重要。有趣的是代谢物 是整体细胞代谢的最终产物。这些是可以轻松监测的小分子 在体液中审查疾病表型。安静的是，我们的小组正在建立 利用代谢物进一步监测肿瘤。因此，我们目前的建议旨在确定DNA加合物和 BCA吸烟者中的相关代谢物，并使用这些信息来开发标记物以尽早识别 患有侵略性膀胱癌风险的患者。进一步将使临床医生能够接受 关于对个性化医学的更适当治疗策略的明智决定。