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

背景：靶向抗癌治疗的发展需要了解预测肿瘤反应的标志物，确定肿瘤的致癌驱动因素，并证明调查药物对其靶点的有效性。在项目的这一部分，我们致力于从患者身上获得正确的细胞，识别致癌驱动因素，并通过药效学标记来证明药物的活性。技术、试验设计、开发和验证。我们开发，验证，并实施分析临床标本使用电化学发光（ECL）为基础的免疫分析。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，我们正在参与NCI-CCR的10个临床方案。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。1)李建军，李建军，李建军，李建军，李建军，李建军，李建军。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。2)李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军。中国。巨蟹座，17:1190-9,2011。3) 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。4)陈建军，陈建军，陈建军，陈建军，陈建军，黄酮类化合物对hif -1 α表达的影响。中国农业大学学报，30(2):481 - 481,2010。5)马志强，马志强，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军，李建军。雷帕霉素治疗骨肉瘤的临床研究进展。PLoS ONE。5: e11013, 2010。3。循环肿瘤细胞新技术及应用的发展。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。我们开始开发分离和表征CTC的新技术。利用CTC鉴定癌症遗传变化的几个下游应用也得到了发展。我们将于下个月开始该项目的临床评估阶段。

Background: The development of targeted anti-cancer therapies requires the understanding the markers predictive of response, the identification of oncogenic drivers of the tumors, and the demonstration of the effectiveness of the investigation agents against their targets. In this part of the project, we are engaged in obtaining the right cells from patients, identifying the oncogenic drivers, and in demonstrating the activities of the agents with pharmacodynamic markers. I. Technology, 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 10 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. 1) 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. 2) 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. 3) 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. 4) Terzuoli E, Puppo M, Rapisarda A, Uranchimeg B, Cao L, Burger AM, Ziche M, Melillo G. Aminoflavone, a ligand of the aryl hydrocarbon receptor, inhibits HIF-1alpha expression in an AhR-independent fashion. Cancer Res. 70: 6837-48, 2010. 5) Paoloni MC, Mazcko C, Fox E, Fan T, Lana S, Kisseberth W, Vail DM, Nuckolls K, Osborne T, Yalkowsy S, Gustafson D, Yu Y, Cao L, Khanna C. Rapamycin pharmacokinetic and pharmacodynamic relationships in osteosarcoma: a comparative oncology study in dogs. PLoS ONE. 5: e11013, 2010. 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. We started the development of novel technologies for the isolation and characterization CTC. Several of downstream applications in using CTC for the identification of cancer genetic changes have also been developed. We are set to start the clinical evaluation phase of the project in the coming month.