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

项目摘要/摘要 吸烟是膀胱癌(BCA)的主要危险因素。有吸烟史或吸烟史的患者 患BCA的可能性要高出三倍。众所周知，吸烟还具有潜在的剂量依赖性。 对BCA的分级和分期的影响，高剂量吸烟者有更多的侵袭性疾病。此外, 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 基于患BCA风险的吸烟者是缺乏的。此外，攻击性的预测性标记 大剂量吸烟者中的BCA也缺乏。这个应用程序的中心目标是描述 在吸烟相关的BCA中观察到DNA加合物和生化变化，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记物和治疗策略。香烟 烟雾含有许多外来化合物，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 异源生物的代谢和排泄在尿液中。我们强有力的初步数据表明DNA发生了改变 BCA吸烟者异物代谢的加合物和重编程。这种效果被夸大了，因为 香烟烟雾的成分，包括尼古丁。使用一种新的代谢组学方法，我们早先 研究表明，BCA与一种独特的代谢特征有关。从患者的角度来看，这是 重要的是能够非侵入性地测量尿液等体液中的这些标志物。有趣的是，代谢物 是整个细胞新陈代谢的最终产物。这些都是很容易监测的小分子 在体液中询问有问题的疾病表型。安静地挑衅地，我们的小组正在建立 利用代谢产物进一步监测肿瘤。因此，我们目前的提案旨在识别DNA加合物和 BCA吸烟者的相关代谢产物，并利用这些信息开发早期识别BCA吸烟者 有患侵袭性膀胱癌风险的患者。进一步将使临床医生能够采取 对个性化医疗的更合适的治疗策略做出明智的决定。

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.