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

循环肿瘤细胞捕获

• 批准号: 8192948
• 负责人: RICHARD JAMES COTE
• 金额: $ 48.46万
• 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 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8192948
• 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; 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; Goals; Health; 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; Regimen; 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; 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; phase 3 study; progenitor; prognostic; 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，也是癌症死亡率的第二高。迫切需要新的预后和预测性生物标志物，以更好地告知我们的治疗决策。最近的研究表明，周围血液循环肿瘤细胞（CTC）的定量预测晚期前列腺癌的治疗和总体生存的反应。但是，CTC收集的当前方法受到低收益，复杂的技术和昂贵的设备的限制，并且几乎没有关于CTC本身的表型信息。为了解决这些局限性，我们开发了一种新的微滤器装置，该设备适合普通注射器并可靠地陷阱，并从外围血液中富集了CTC种群，从而实现了枚举并进一步研究这些细胞，例如对治疗靶靶标的表征。我们的假设是，在治疗方案过程中，CTC的定量和表征可以确定预后，并预测对治疗的反应，并且在大型临床试验环境中，微孔滤器可以作为CTC收集，定量和表型分析的简单但可靠的新平台。为了检验这一假设，我们提出了一项相关研究，该研究将“ piggyback”在S0421上，S0421是一种活跃的Swog合作组协议，研究Atrasentan与Docetaxel在抗Castration抗性前列腺癌中结合使用。该提案已由SWOG审查，并获得了执行批准。在3个时间点，通过S0421，预处理（第1天）和治疗期间（第21和63天，即在第二次处理的第二和第四处理时），将通过微滤器进行绘制并处理血样，并将捕获的CTC进行分析，以解决以下特定目标：1。临床结果和对治疗的反应？随着微滤器CTC捕获的进一步验证，将使用FDA批准的单元搜索CTC收集平台分析并行样品； 2。相关生物标志物在微滤器捕获的CTC上的表达是否可以预测临床结果和对治疗的反应？我们将针对阿特拉森坦反应，多西他赛反应的Atrasentan反应，特异性评估内皮素受体A和侵袭性祖细胞/转移表型的CD44；和3。富含微孔滤液的细胞中端粒酶活性的存在和水平是否与捕获的CTC的存在和数量相关，并且是否可以用于预测临床结果和对治疗的反应？总而言之，我们的目标是确定在我们的新型平台上捕获的CTC的数量和特征是否可以预测S0421中的临床结果和对治疗的反应。最终，这项研究的结果将大大为我们在前列腺癌中的治疗决策提供明显的依据，并深刻增强我们实时评估治疗疗效的能力，从而构成了针对优化的，基于证据的，基于循证的个性化患者管理的大步迈进。公共卫生相关性：我们建议使用一种新型的微孔设备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的治疗反应和存活的标志物，使用新型的微孔装置捕获并丰富了Swog临床试验中招募的患者的循环和循环的CTC，S0421。我们将分析CTC是否计数，相关生物标志物的表达以及富含微孔的CTC中的端粒酶活性（已建立的癌症标志物）可以预测结果和对治疗的反应。我们预计这项研究将大大帮助前列腺癌管理并增强治疗功效的实时评估。