Design, Develop, Validate, and Implement Biomarkers for Clinical Investigations

I.生物标记物检测的设计、开发和验证我们开发、验证和实施基于电化学发光(ECL)的免疫分析方法对临床标本进行检测。这是当今最灵敏、最定量的免疫分析技术平台。ECL平台非常适合这项持续的任务，因为它提供了高度的灵活性、稳定性和可靠性。它能够用有限数量的临床标本进行多重分析，在一次检测中很好地确定总蛋白和磷酸蛋白的水平。由于临床样本可能差异很大，因此将这些样本正常化超过总蛋白浓度的能力对于生成具有统计学意义的患者样本数据至关重要。目前，我们开发、验证和利用了广泛的生物标记物，包括血管生成因子、细胞因子、细胞表面受体、细胞内磷蛋白和凋亡生物标记物。最近完成的生物标志物研究目前，我们在NCI-CCR参与了16项临床方案。对于这些临床试验中的许多，我们帮助设计、开发、验证和实施用于相关分析研究的定制生物标记物分析。这些生物标志物的评估通常构成研究药物临床研究的关键部分。以下是我们在NCI进行的生物标记物分析研究中的一些例子。几份手稿正在准备中。1.Kalra N，Zhang J，Yu Y，Ho M，Merino M，曹L，Hassan R。抗胰岛素样生长因子I受体单抗在间皮瘤中的疗效与胰岛素生长因子I受体位置/细胞高度相关。《国际癌症杂志》。2012年。2.Speranza G，Gutierrez ME，Kummar S，Strong JM，Parker RJ，Collins J，Yu Y，曹L，Murgo AJ，Doroshow JH，Chen A.合成三萜类化合物2-氰基-3，12-二氧杂环烯-1，9-二烯-28-酸在晚期实体瘤中的第一阶段研究。癌症化学物质。药水。2012年，69：431-8。3.贾康内G、拉詹·A、伯曼·A、凯利·RJ、萨博·E、洛佩兹-查韦斯·A、特雷佩尔·J、李·MJ、曹操·L、埃斯皮诺莎-德尔加多一世、斯皮特勒·J、罗勒·PJ。贝力诺斯特治疗复发或难治性晚期胸腺上皮肿瘤患者的II期研究。J·克莱恩。奥科尔。29：2052-9,2011。4.凯利·RJ、拉詹·A、力量J、洛佩兹-查韦斯·A、基恩·C、曹操·L、于洋、乔伊克·P、特尔克贝·B、拉菲尔德·M、习·L、斯坦伯格·SM、赖特·JJ、库马尔·S、古铁雷斯·M、贾克内·G。接受索拉非尼治疗的晚期非小细胞肺癌患者的KRAS突变、血管生成生物标志物和磁共振成像的评估。克莱恩。癌症研究报告17：1190-9,2011。5.库马尔·S、古铁雷斯·ME、陈A、特尔克贝·IB、艾伦·D、霍内弗·YR、朱瓦拉·L、曹操·L、于洋、金日成、特雷佩尔·J、陈H、乔伊克·P、梅里洛·G、默戈·AJ、柯林斯·J、多萝西·J、多洛西奥·JVandetanib和贝伐单抗的I期试验评估了实体肿瘤和淋巴瘤成人患者中的血管内皮生长因子和表皮生长因子信号转导通路。欧元。J.癌症。2011年，47：997-1005。循环肿瘤细胞新技术和应用的发展循环肿瘤细胞(CTC)用于癌症基因和生物标志物分析的能力为改变临床试验和患者管理提供了潜力。在CTC纯化和随后的CTC细胞的遗传分析方面做了大量的努力，这导致了这一领域非常有希望的进展。在过去的一年里，我们利用CTC技术启动了4项临床试验，包括两项针对肺癌和前列腺癌的概念验证试验；以及两项药物试验，旨在为使用CTC指导患者治疗提供首创的新技术。我们预计将加倍努力，并在不久的将来取得一些重大进展。两份手稿正在准备中。

I. Biomarker Assay Design, Development, and Validation We develop, validate, and implement assays for clinical specimens using electrochemiluminescence (ECL)-based immunoassays. This is the most sensitive and quantitative immunoassay technology platform today. The ECL platform is well suited for this ongoing task because it offers a high degree of flexibility, stability and reliability. It is capable of multiplex analysis to determine the levels of total and phospho-proteins in a single assay well using a limited amount of clinical specimens. Because clinical samples may vary dramatically, the ability to normalize these samples beyond total protein concentration is critical in generating statistically significant data with patient specimens. At the present, we developed, validated and utilized a wide range of biomarker assays, including angiogenic factors, cytokines, cell surface receptors, intracellular phosphoproteins and apoptotic biomarkers. II. Recently Completed Biomarker Studies Currently, we are engaged with 16 clinical protocols at NCI-CCR. For many of these clinical trials, we helped to design, develop, validate, and implement customized biomarker assays for correlative analytical studies. The evaluation of these biomarkers often constitutes a pivotal part of the clinical study for investigational agents. The following are some examples in the studies that we contributed with biomarker analysis at NCI. Several manuscripts are in preparation. 1. Kalra N, Zhang J, Yu Y, Ho M, Merino M, Cao L, Hassan R. Efficacy of anti-insulin-like growth factor I receptor monoclonal antibody cixutumumab in mesothelioma is highly correlated with insulin growth factor-I receptor sites/cell. International journal of cancer. 2012. 2. Speranza G, Gutierrez ME, Kummar S, Strong JM, Parker RJ, Collins J, Yu Y, Cao L, Murgo AJ, Doroshow JH, Chen A. Phase I study of the synthetic triterpenoid, 2-cyano-3, 12-dioxoolean-1, 9-dien-28-oic acid (CDDO), in advanced solid tumors. Cancer Chemother. Pharmacol. 69: 431-8, 2012. 3. Giaccone G, Rajan A, Berman A, Kelly RJ, Szabo E, Lopez-Chavez A, Trepel J, Lee MJ, Cao L, Espinoza-Delgado I, Spittler J, Loehrer PJ. Phase II Study of Belinostat in Patients With Recurrent or Refractory Advanced Thymic Epithelial Tumors. J. Clin. Oncol. 29: 2052-9, 2011. 4. Kelly RJ, Rajan A, Force J, Lopez-Chavez A, Keen C, Cao L, Yu Y, Choyke P, Turkbey B, Raffeld M, Xi L, Steinberg SM, Wright JJ, Kummar S, Gutierrez M, Giaccone G. Evaluation of KRAS Mutations, Angiogenic Biomarkers, and DCE-MRI in Patients with Advanced Non-Small-Cell Lung Cancer Receiving Sorafenib. Clin. Cancer Res. 17: 1190-9, 2011. 5. Kummar S, Gutierrez ME, Chen A, Turkbey IB, Allen D, Horneffer YR, Juwara L, Cao L, Yu Y, Kim YS, Trepel J, Chen H, Choyke P, Melillo G, Murgo AJ, Collins J, Doroshow JH. Phase I trial of vandetanib and bevacizumab evaluating the VEGF and EGF signal transduction pathways in adults with solid tumours and lymphomas. Eur. J. Cancer. 47: 997-1005, 2011. III. Development of novel technology and applications with circulating tumor cells The ability of use circulating tumor cells (CTC) for cancer genetic and biomarker analysis offer the potential to transform clinical trials and patient management. Substantial effort was made towards CTC purification and subsequently genetic analysis of the CTC cells which results highly promising advances in this field. We have initiated 4 clinical trials in the past year with our CTC technologies, including two prove-of-concept trials with lung and prostate cancer; as well as two drug trials with a goal to provide first-of-the-kind novel enablement for using CTC to guide patient treatment. We expect to double down our effort and to have some significant advances in the near future. Two manuscripts are in preparation.