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

设计、开发、验证和实施用于临床研究的生物标志物

• 批准号: 8350121
• 负责人: Liang Cao
• 金额: $ 33.05万
• 依托单位: DIVISION OF BASIC SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8350121
• 关键词: Adult; Angiogenic Factor; Apoptotic; BAY 54-9085; Biological; Biological Assay; Biological Markers; CCR; Canis familiaris; Cell Surface Receptors; Cells; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Correlative Study; Data; Development; Drug Kinetics; EGF gene; Effectiveness; Enrollment; Evaluation; Foxes; Goals; HIF1A gene; Immunoassay; Investigation; KRAS2 gene; Laboratories; Lymphoma; Magnetic Resonance Imaging; Malignant Neoplasms; Modeling; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Patients; Pharmacodynamics; Phase; Phase I Clinical Trials; Phosphoproteins; Proteins; Recurrence; Refractory; Sampling; Signal Transduction Pathway; Sirolimus; Solid Neoplasm; Specimen; Technology; Therapeutic; Thymus Epithelial Neoplasm; Validation; Vascular Endothelial Growth Factors; aryl hydrocarbon receptor ligand; base; bevacizumab; cancer genetics; cancer therapy; comparative; cytokine; design; flexibility; neoplastic cell; new technology; oncology; osteosarcoma; phase 2 study; research clinical testing; response; tumor

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.

背景：靶向抗癌治疗的发展需要了解预测反应的标志物，识别肿瘤的致癌驱动因素，并证明研究试剂针对其靶点的有效性。在该项目的这一部分，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，并展示具有药效学标记的药物的活性。技术、化验设计、开发和验证。我们开发、验证和实施基于电化学发光(ECL)的免疫分析方法用于临床标本的分析。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。二、近期完成的生物标志物研究。目前，我们在NCI-CCR参与了10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。1)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。2)Kelly RJ，Rajan A，Force J，Lopez-Chavez A，Keen C，曹L，Yu Y，Choyke P，Turbey B，Raffeld M，Xi L，Steinberg SM，Wright JJ，Kummar S，Gutierrez M，Giaccon 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。3)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、于勇、金妍儿、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、多萝西·J·H。Vandetanib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。4)芳香烃受体的配体Terzuoli E、Puppo M、Rapisarda A、Urancheig B、CaO L、Burger AM、Ziche M、Melillo G.氨基黄酮能以非AhR方式抑制HIF-1α的表达。癌症研究报告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，曹L，Khanna C.雷帕霉素在骨肉瘤中的药代动力学和药效关系：狗的比较肿瘤学研究。PLOS一号。5：E11013,2010。循环肿瘤细胞的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记物分析的能力提供了改变临床试验和患者管理的潜力。我们开始了CTC分离和表征新技术的开发。在使用CTC鉴定癌症基因变化方面，也开发了几种下游应用。我们准备在下个月开始该项目的临床评估阶段。