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

I.生物标志物检测设计、开发和验证我们使用基于电化学发光（ECL）的免疫分析开发、验证和实施临床标本检测。这是当今最灵敏的定量免疫分析技术平台。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。它能够进行多重分析，以使用有限量的临床标本在单个测定孔中测定总蛋白和磷蛋白的水平。由于临床样本可能差异很大，因此在总蛋白浓度之外对这些样本进行标准化的能力对于生成患者样本的统计学显著数据至关重要。目前，我们开发、验证和利用了广泛的生物标志物检测，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志物。二.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。对于其中的许多临床试验，我们帮助设计、开发、验证和实施了相关分析研究的定制生物标志物检测。这些生物标志物的评价通常构成了研究药物临床研究的关键部分。以下是我们在NCI进行生物标志物分析的研究中的一些示例。几份手稿正在编写中。1. [10]张杰，余勇，何明，美利奴，曹立，哈桑.抗胰岛素样生长因子I受体单克隆抗体cixutumumab治疗间皮瘤的疗效与胰岛素生长因子I受体位点/细胞高度相关。国际癌症杂志。2012. 2. Speranza G，Gutierrez ME，Kummar S，Strong JM，帕克RJ，柯林柯林斯J，Yu Y，Cao L，Murgo AJ，Doroshow JH，Chen A.合成三萜类化合物2-氰基-3，12-二氧代-1，9-二烯-28-酸（CDDO）在晚期实体瘤中的I期研究。癌症化疗。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.贝利司他在复发性或难治性晚期胸腺上皮肿瘤患者中的II期研究。《临床肿瘤学杂志》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.接受索拉非尼治疗的晚期非小细胞肺癌患者KRAS突变、血管生成生物标志物和DCE-MRI的评价Clin. Cancer Res. 17：1190-9，2011. 5. Kummar S，Gutierrez ME，Chen A，Turkbey IB，艾伦D，Horneffer YR，Juwara L，Cao L，Yu Y，Kim YS，Trepel J，Chen H，Choyke P，Melillo G，Murgo AJ，柯林柯林斯J，Doroshow JH.凡德他尼和贝伐珠单抗的I期试验，评估实体瘤和淋巴瘤成人中VEGF和EGF信号转导途径。EUR. J.癌症。47：997-1005，2011.三.循环肿瘤细胞的新技术和应用的开发循环肿瘤细胞（CTC）用于癌症遗传学和生物标志物分析的能力提供了改变临床试验和患者管理的潜力。对CTC纯化和随后的CTC细胞的遗传分析进行了大量的努力，这在该领域产生了非常有前途的进展。在过去的一年里，我们已经利用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型支持。我们期望加倍努力，在不久的将来取得一些重大进展。两份手稿正在编写中。

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.