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

描述（由申请人提供）：前列腺癌是美国男性中最常见的恶性肿瘤，也是癌症死亡率的第二高原因。迫切需要新的预后和预测生物标志物，以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）的定量预测对治疗的反应和晚期前列腺癌的总生存期。然而，目前用于CTC收集的方法受到低产量、复杂技术和昂贵设备的限制，并且它们提供关于CTC本身的表型信息很少。为了解决这些局限性，我们开发了一种新的微过滤器装置，该装置安装在普通注射器上，可以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的定量和表征可以在治疗方案的早期确定预后并预测对治疗的反应，并且微滤器可以在大型临床试验环境中作为CTC收集、定量和表型分析的简单而可靠的新平台。为了验证这一假设，我们提出了一项相关研究，该研究将“搭载”到S 0421上，S 0421是一项研究阿曲生坦与多西他赛联合治疗去势抵抗性前列腺癌的活性SWOG合作组方案。该提案已由SWOG审查，并已获得行政批准。在S 0421预先指定的3个时间点，即治疗前（第1天）和治疗期间（第21天和第63天，即4次治疗中的第2次和第4次治疗时），将抽取血液样本并通过微滤器装置进行处理，并分析捕获的CTC以解决以下特定目的：1.绝对CTC计数和治疗后CTC计数的变化能否准确预测临床结局和治疗反应？作为微滤器CTC捕获的进一步验证，将使用FDA批准的Cell Search CTC收集平台分析平行样品; 2.相关生物标志物在微滤器捕获的CTC上的表达是否可预测临床结果和对治疗的反应？我们将具体评估内皮素受体A对阿曲生坦的响应，III型2-微管蛋白对多西他赛的响应，以及⑶ 44对侵袭性祖细胞/转移表型;以及3.微滤器富集细胞中端粒酶活性（一种既定的癌症标志物）的存在和水平是否与捕获的CTC的存在和数量相关，以及它是否可用于预测临床结果和对治疗的反应？总之，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S 0421中的临床结果和对治疗的反应。最终，这项研究的结果将为我们的前列腺癌治疗决策提供重要信息，并大大提高我们在真实的时间内评估治疗效果的能力，从而向优化，循证，个性化的患者管理迈出了一大步。公共卫生相关性：我们建议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期的标志物，使用新型微滤器装置捕获并富集SWOG临床试验S 0421中招募的患者的循环CTC。我们将分析微滤器富集的CTC中的CTC计数、相关生物标志物的表达和端粒酶活性（一种既定的癌症标志物）是否可以预测治疗结果和应答。我们希望这项研究能显著帮助前列腺癌的管理和提高治疗效果的真实的时间评估。

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.