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

我们开发、验证和实施基于电化学发光（ECL）免疫分析的临床标本分析。这是当今最灵敏、最定量的免疫分析技术平台。ECL平台非常适合这项正在进行的任务，因为它提供了高度的灵活性、稳定性和可靠性。它能够多重分析，以确定总蛋白和磷酸化蛋白的水平，在一个单一的分析井使用有限数量的临床标本。由于临床样本可能会有很大的差异，因此对这些超过总蛋白浓度的样本进行标准化处理的能力对于产生具有统计意义的患者样本数据至关重要。目前，我们开发、验证和使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、细胞内磷酸化蛋白和凋亡生物标志物。2。最近完成的生物标志物研究目前，我们正在NCI-CCR参与16项临床方案。对于许多此类临床试验，我们帮助设计、开发、验证和实施相关分析研究的定制生物标志物测定。这些生物标志物的评估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的生物标志物分析研究中的一些例子。几份手稿正在准备中。1. Kalra N，张军，于颖，何敏，Merino M，曹玲，Hassan R.抗胰岛素样生长因子I受体单克隆抗体环妥珠单抗治疗间皮瘤的疗效与胰岛素样生长因子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, Parker RJ, Collins J, Yu Y, Cao L, Murgo AJ, Doroshow JH, Chen A.合成三萜-2 -氰基- 3,12 -二氧基- 1,9 -二烯-28-oic酸（CDDO）在晚期实体瘤中的临床研究。癌症Chemother。中国医学杂志，2012,31(4):431- 438。3. 贾科内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。Belinostat治疗复发或难治性晚期胸腺上皮肿瘤的II期研究。j .中国。中国生物医学工程学报，29(9):2052- 2049,2011。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.晚期非小细胞肺癌患者KRAS基因突变、血管生成生物标志物和DCE-MRI的评价。中国。巨蟹座，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。vandetanib和bevacizumab的I期临床试验评估成人实体瘤和淋巴瘤患者的VEGF和EGF信号转导途径。欧元。[j] .中国医学杂志，2011。3。利用循环肿瘤细胞（CTC）进行癌症遗传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。对CTC细胞的纯化和遗传分析进行了大量的研究，在这一领域取得了很大的进展。在过去的一年里，我们已经启动了4项CTC技术的临床试验，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，目的是为使用CTC指导患者治疗提供首创的新支持。我们希望加倍努力，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.