Clin.Relevance of Circulat.Tumor Cells in Bladder Cancer

描述（由申请人提供）：本提案的主要目的是确定膀胱癌患者循环肿瘤细胞（CTC）检测的临床相关性。具体目的是：1)比较浅表性膀胱癌患者与转移性膀胱癌患者中尿白蛋白（i - il）、角蛋白（k19和k20）、表皮生长因子受体（EGFR）的CTC检出率；2)探讨这些分子标志物在原发性和转移性组织沉积物中的表达与CTC检出率的关系。我们建议使用逆转录聚合酶链式反应（RT-PCR）检测50例浅表肿瘤患者（微转移可能性低）和50例严重转移疾病患者（微转移可能性高）的血液样本。所有患者将在四周内采样三次，以提高CTC阳性检出率。然后，CTC RT-PCR将在检测时与疾病的存在相关联，以确定最具临床信息的标记物，这些标记物为微转移的存在提供了最佳的敏感性、特异性和总体预测价值。将使用免疫组织化学和RT-PCR对目标1中列出的患者标本中分子标记物的组织表达进行评估，然后将结果与CTC的RT-PCR结果相关联。这一分析将有助于我们了解这些标志物在膀胱癌进展过程中的组织表达变化，以及这些变化与血液中CTC的产生有何关系。我们的初步数据清楚地表明，纽约大学医学院和纪念斯隆-凯特琳癌症中心合作开展拟议工作的可行性。这种合作的工作使研究具有强大的实验室和临床设施，这是成功进行这种类型的翻译研究所必需的。我们计划将该项目作为一期试点研究，以响应“泌尿外科试点和可行性计划”计划公告#02-013；我们打算收集足够的数据，以便在一项II期前瞻性研究中研究CTC的发展，该研究将检查肌肉侵袭性疾病患者手术切除肿瘤后CTC检测与复发之间的关系。我们预计三期标志物开发是一项多机构研究，目标是在考虑向FDA申请将CTC检测整合为膀胱癌患者护理管理标准的一部分之前，独立验证和验证这种相关性。

DESCRIPTION (provided by applicant): The main objective of this proposal is to define the clinical relevance of detecting circulating tumor cells (CTC) in bladder cancer patients. The specific aims are: 1) To compare the detection rates of CTC for uroplakins (I-Ill), keratins (k19 and k20), and Epidermal Growth Factor Receptor (EGFR) in patients with superficial bladder cancer versus those with metastatic bladder cancer, and 2) To examine the relation between the expression of these molecular markers in primary and metastatic tissue deposits and their CTC detection rate. We propose to test blood samples from 50 bladder cancer patients with superficial tumors (expected to have low likelihood of micrometastases) and 50 with grossly metastatic disease (expected to have a high likelihood of micrometastases) using Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). All patients will be sampled three times over a four week period to increase the positive CTC detection rate. The CTC RT-PCR will be then correlated with presence of disease at the time of the assay to define the most clinically informative marker(s) that provide the best sensitivity, specificity and overall predictive value for the presence of micrometastases. The tissue expression of the molecular markers will be assessed using immunohistochemistry as well as RT-PCR in specimens obtained from patients outlined in aim 1, and the results will then be correlated with the RT-PCR results for CTC. This analysis will help us to understand changes in the tissue expression of these markers during the progression of bladder cancer and how these changes are related to seeding of CTC in the blood. Our preliminary data clearly demonstrate the feasibility of conducting the proposed work as a collaborative effort between New York University School of Medicine and Memorial Sloan-Kettering Cancer Center. This cooperative work endows the study with the strong laboratory and clinical facilities that are necessary for the successful conduct of this type of translation research. We plan this project as a phase I pilot study, in response to the "Pilot and Feasibility Program in Urology" Program Announcement #02-013; we intend to generate sufficient data in order to pursue the development of CTC in a phase II prospective study that will examine the correlation between CTC detection and recurrence in patients with muscle invasive disease following surgical resection of the tumor. We foresee phase III marker development as a multi-institutional study with the goals of independently verifying and validating this correlation prior to considering an application to the FDA for integrating CTC detection as part of the standard of care management for bladder cancer patients.