Metabolomic discovery and validation of urinary biomarkers for kidney cancer

描述(申请人提供)：肾癌(也称为肾细胞癌[RCC])在36,000名患者中被诊断出来，是美国每年11-13,000人死亡的原因；不幸的是(由于未知的原因)，这种疾病在所有群体中的发病率都在增加。三分之一的病例，其中许多是无症状的，在确诊时是转移性的，目前没有可用的生物流体诊断测试或一旦确诊就进行适当的治疗。考虑到肾脏与尿液的关系，RCC非常适合用于尿液标志物的鉴定。在这个修订的提案中，我们将利用代谢组学的新科学来发现尿代谢物的模式，这些代谢物可以作为肾癌高危患者的生物标志物。我们将通过使用肾癌组织和细胞系，使用途径和网络分析来确认这种疾病中哪些代谢途径出错，从而支持我们的生物标记物发现。最后，我们将在肾癌非肾癌患者的新样本中测试我们的生物标记物，包括非恶性肾脏疾病的对照患者以及非肾癌患者。对于这次修订，我们增加了所有要求的初步数据，从而改进了提案。我们还提交了两份与肾细胞癌代谢组学和蛋白质组学相关的出版物。我们的建议非同寻常，因为我们汇集了一支独特的合作者队伍：一名细胞生物学家，同时也是临床科学家肾病学家(Weiss博士)，一名蛋白质组学和基因组学专家(Perroud博士)，四名代谢组学专家(DRS Fiehn，Hammock，Michelmore和Grant)，两名生物统计学家(Kim和Rocke博士)，两名肿瘤病理学家(Grize和Borowsky博士)，以及两名泌尿外科肿瘤学家(De Vere White和Evans博士)，利用代谢组学来解决难以诊断的癌症的诊断和治疗问题，这种癌症的发病率正在上升，目前的治疗方案令人沮丧。我们感到高兴的是，评审员同意我们提案中的实验是合理的。这些实验的成功完成将导致诊断方面的重大进步，并最终为这种疾病选择最佳治疗方案。我们将是第一个描述这项技术在泌尿系统恶性肿瘤中的应用，也是第一个在任何癌症中使用这项技术的人之一。此外，我们的工作可以作为使用代谢组学收集各种癌症的致癌途径和网络数据的模型。

DESCRIPTION (provided by applicant): Kidney cancer (also known as renal cell carcinoma [RCC]) is diagnosed in 36,000 patients and is the cause of death of 11-13,000 individuals yearly in the US; unfortunately (and for unknown reasons), the incidence of this disease is increasing in all groups. One-third of cases, many of whom are asymptomatic, are metastatic at diagnosis and there is currently no available biofluid diagnostic test or adequate treatment once diagnosed. Given the relationship of the kidney to the urine, RCC is ideally suited for identification of urinary markers. In this revised proposal, we will exploit the new science of metabolomics to discover a pattern of urinary metabolites which serve as biomarkers for RCC in patients who are at high risk for this disease. We will support our biomarkers discovery by using pathway and network analysis to confirm which metabolic pathways go awry in this disease, using RCC tissues and cell lines. Finally, we will test our biomarkers in new samples from both RCC non-RCC patients, including as controls patients with non-malignant renal disease as well as patients who have non-renal cancers. For this revision, we have improved the proposal by adding all of the requested preliminary data. We have also submitted two publications related to RCC metabolomics as well as proteomics. Our proposal is extraordinary in that we have assembled a unique cadre of collaborators: a cell biologist who is also a clinician- scientist nephrologist (Dr. Weiss), a proteomics and genomics expert (Dr. Perroud), four metabolomics experts (Drs Fiehn, Hammock, Michelmore, and Grant), two biostatisticians (Drs. Kim and Rocke), two oncologic pathologists (Drs. Grizzle and Borowsky), and two urologic oncologists (Drs. De Vere White and Evans) to utilize metabolomics to tackle the problem of diagnosis and treatment of a cancer which is difficult to diagnose, whose incidence is increasing, and for which current treatment options are dismal. We are pleased that the reviewers agreed that the experiments in our proposal were sound. Successful completion of these experiments will result in a major advance in diagnosis as well as, ultimately, the selection of optimal treatment regimens for this disease. Ours will be the first described use of this technology in urologic malignancy, and one of the first to exploit this technology in any cancer. Furthermore, our work can serve as a model for using metabolomics to glean oncogenic pathway and network data from a variety of cancers.