Circulating Tumor Cell Capture & Analysis in a Multi-Center Prostate Cancer Trial

循环肿瘤细胞捕获

• 批准号: 7700441
• 负责人: RICHARD JAMES COTE
• 金额: $ 52.44万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-18 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7700441
• 关键词: ABT-627; Address; Affect; Aftercare; American; Androgens; Atrasentan; Bioavailable; Biological; Biological Assay; Biological Markers; Blood; Blood specimen; Breast; CD44 gene; Calcitriol; Cancer Etiology; Cancer Patient; Castration; Cell Count; Cell surface; Cells; Cessation of life; Characteristics; Clinical; Clinical Trials; Collaborations; Collection; Colon Carcinoma; Colorectal Cancer; Complex; Correlative Study; Data; Detection; Development; Devices; Dimensions; Disease; Disseminated Malignant Neoplasm; Early treatment; Endothelin; Endothelin Receptor; Enrollment; Enzymes; Epidermal Growth Factor Receptor; Equipment; Evaluation; Event; FDA approved; Genetic screening method; Genitourinary system; Genus Cola; Goals; Hematopoietic; HercepTest; Heterogeneity; Hormones; Immunofluorescence Immunologic; Immunohistochemistry; Institutes; Institution; Life; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Measurement; Measures; Membrane; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Methods; Molecular; Monitor; Multi-Institutional Clinical Trial; Mutation; Outcome; Pain; Pathway interactions; Patients; Phase III Clinical Trials; Phenotype; Placebo Control; Placebos; Population; Predictive Value; Process; Progression-Free Survivals; Prostate; Prostate Cancer Vaccine; Prostate-Specific Antigen; Proteins; Protocols documentation; Randomized; Refractory; Relative (related person); Reporting; Resistance; Resistance development; Sampling; Second Primary Neoplasms; Serum; Serum Markers; Southwest Oncology Group; Speed; Surrogate Markers; Syringes; TACSTD2 gene; Techniques; Telomerase; Testing; Therapeutic; Time; Time Study; Treatment Efficacy; Treatment Protocols; Tubulin; Validation; base; bevacizumab; cancer stem cell; chemotherapy; cost; deprivation; docetaxel; evidence base; improved; inhibitor/antagonist; malignant breast neoplasm; men; mortality; neoplastic cell; novel; novel strategies; oncology; outcome forecast; parylene; peripheral blood; progenitor; prognostic; public health relevance; response; response marker; therapeutic target; time use; treatment duration; treatment response; trend

DESCRIPTION (provided by applicant): Prostate cancer is the most common malignancy and the second highest cause of cancer mortality in American men. New prognostic and predictive biomarkers are urgently needed to better inform our treatment decisions. Recent studies have demonstrated that quantification of peripheral blood circulating tumor cells (CTCs) predicts response to therapy and overall survival in advanced prostate cancer. However, present methods for CTC collection are limited by low yield, complex techniques, and expensive equipment, and they provide little phenotypic information about the CTCs themselves. To address these limitations, we have developed a new microfilter device that is fitted to an ordinary syringe and reliably traps and enriches the CTC population from peripheral blood, enabling enumeration and further study of these cells, such as characterization of therapeutic targets. It is our hypothesis that quantification and characterization of CTC can determine prognosis and predict response to therapy early in the course of the therapeutic regimen, and that the microfilter can serve as a simple yet reliable new platform for CTC collection, quantification, and phenotypic analysis in a large clinical trial setting. To test this hypothesis, we propose a correlative study that would "piggyback" onto S0421, an active SWOG cooperative group protocol studying atrasentan in combination with docetaxel in castration resistant prostate cancer. This proposal has been reviewed by SWOG and has received executive approval. At 3 time points pre-designated by S0421, pre-treatment (day 1) and during treatment (days 21 and 63, that is at the time of the second and fourth of 4 treatments), blood samples will be drawn and processed through the microfilter device, and the captured CTCs will be analyzed to address the following specific aims: 1. Do absolute CTC counts and post-treatment changes in CTC counts accurately predict clinical outcome and response to therapy? As further validation of microfilter CTC capture, parallel samples will be analyzed using the FDA approved Cell Search CTC collection platform; 2. Does the expression of relevant biomarkers on microfilter-trapped CTCs predict clinical outcome and response to therapy? We will specifically assess endothelin receptor A for atrasentan response, type III 2-tubulin for docetaxel response, and CD44 for an aggressive progenitor/metastatic phenotype; and 3. Does the presence and level of telomerase activity (an established cancer marker) in microfilter-enriched cells correlate with the presence and number of captured CTCs, and can it be used to predict clinical outcome and response to therapy? In summary, our goal will be to determine if the quantity and characteristics of CTCs captured on our novel platform can predict clinical outcome and response to therapy in S0421. Ultimately, the results of this study will significantly inform our treatment decisions in prostate cancer and profoundly enhance our ability to assess therapeutic efficacy in real time, thus constituting a major stride towards optimized, evidence-based, individualized patient management. PUBLIC HEALTH RELEVANCE: We propose to quantify and characterize peripheral blood circulating tumor cells (CTCs) as a marker to predict therapeutic response and survival in advanced prostate cancer using a novel microfilter device that traps and enriches circulating CTCs in patients enrolled in the SWOG clinical trial, S0421. We will analyze if CTC counts, expression of relevant biomarkers, and telomerase activity (an established cancer marker) in microfilter- enriched CTCs can predict outcome and response to therapy. We expect this study to significantly help prostate cancer management and enhance real time assessment of therapeutic efficacy.

描述（由申请人提供）：前列腺癌是美国男性最常见的恶性肿瘤，也是导致美国男性癌症死亡的第二大原因。迫切需要新的预后和预测生物标志物来更好地为我们的治疗决策提供信息。最近的研究表明，外周血循环肿瘤细胞 (CTC) 的定量可以预测晚期前列腺癌的治疗反应和总体生存率。然而，目前的 CTC 收集方法受到产量低、技术复杂和设备昂贵的限制，并且它们提供的有关 CTC 本身的表型信息很少。为了解决这些限制，我们开发了一种新的微过滤装置，该装置安装在普通注射器上，能够可靠地捕获和富集外周血中的 CTC 群体，从而能够对这些细胞进行计数和进一步研究，例如治疗靶点的表征。我们的假设是，CTC 的量化和表征可以在治疗方案过程的早期确定预后并预测对治疗的反应，并且微过滤器可以作为大型临床试验环境中 CTC 收集、量化和表型分析的简单而可靠的新平台。为了检验这一假设，我们提出了一项相关研究，该研究将“搭载”S0421，这是一项活跃的 SWOG 合作小组协议，研究阿曲生坦联合多西紫杉醇治疗去势抵抗性前列腺癌。该提案已得到 SWOG 审查并获得行政批准。在S0421预先指定的3个时间点，治疗前（第1天）和治疗期间（第21天和第63天，即4次治疗中的第二次和第四次），将抽取血样并通过微过滤装置进行处理，并对捕获的CTC进行分析，以实现以下具体目的： 1. 准确预测绝对CTC计数和治疗后CTC计数的变化 临床结果和治疗反应？作为微过滤器 CTC 捕获的进一步验证，平行样品将使用 FDA 批准的 Cell Search CTC 收集平台进行分析； 2. 微过滤器捕获的 CTC 上相关生物标志物的表达是否可以预测临床结果和治疗反应？我们将专门评估内皮素受体 A 的阿曲生坦反应、III 型 2-微管蛋白的多西他赛反应以及 CD44 的侵袭性祖细胞/转移表型； 3. 微过滤器富集的细胞中端粒酶活性（一种已确定的癌症标记物）的存在和水平是否与捕获的 CTC 的存在和数量相关，并且它可以用于预测临床结果和对治疗的反应吗？总之，我们的目标是确定我们的新平台上捕获的 CTC 的数量和特征是否可以预测 S0421 的临床结果和治疗反应。最终，这项研究的结果将为我们在前列腺癌的治疗决策中提供重要信息，并深刻增强我们实时评估治疗效果的能力，从而朝着优化、循证、个体化的患者管理迈出一大步。公共健康相关性：我们建议使用一种新型微过滤装置来量化和表征外周血循环肿瘤细胞 (CTC)，作为预测晚期前列腺癌治疗反应和生存的标志物，该装置捕获并富集参加 SWOG 临床试验 S0421 的患者的循环 CTC。我们将分析微过滤器富集的 CTC 中的 CTC 计数、相关生物标志物的表达和端粒酶活性（一种已确定的癌症标志物）是否可以预测结果和对治疗的反应。我们期望这项研究能够显着帮助前列腺癌的管理并增强治疗效果的实时评估。